Medical device rapid drug releasing coatings comprising oils, fatty acids and/or lipids

ABSTRACT

The invention relates to a coated medical device for rapid delivery of a therapeutic agent to a tissue in seconds to minutes. The medical device has a layer overlying the exterior surface of the medical device. The layer contains a therapeutic agent, at least one of an oil, a fatty acid, and a lipid, and an additive. In certain embodiments, the additive has a hydrophilic part and a drug affinity part, wherein the drug affinity part is at least one of a hydrophobic part, a part that has an affinity to the therapeutic agent by hydrogen bonding, a part that has an affinity to the therapeutic agent by charge, and a part that has an affinity to the therapeutic agent by van der Waals interactions. In embodiments, the additive is at least one of a surfactant and a chemical compound. In further embodiments, the chemical compound is water-soluble.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.13/846,104 filed Mar. 18, 2013, which is a continuation of Ser. No.12/123,951, filed May 20, 2008, now U.S. Pat. No. 8,414,526 issued Apr.9, 2013, which is a continuation-in-part of application Ser. No.11/942,452, filed Nov. 19, 2007, now U.S. Pat. No. 8,414,909 issued Apr.9, 2013, which claims the benefit of priority of U.S. ProvisionalApplication No. 60/860,084, filed on Nov. 20, 2006, U.S. ProvisionalApplication No. 60/880,742, filed Jan. 17, 2007, U.S. ProvisionalApplication No. 60/897,427, filed on Jan. 25, 2007, U.S. ProvisionalApplication No. 60/903,529 filed on Feb. 26, 2007, U.S. ProvisionalApplication No. 60/904,473 filed Mar. 2, 2007, U.S. ProvisionalApplication No. 60/926,850 filed Apr. 30, 2007, U.S. ProvisionalApplication No. 60/981,380 filed Oct. 19, 2007, and U.S. ProvisionalApplication No. 60/981,384 filed Oct. 19, 2007, the disclosures of allof which are incorporated by reference herein.

FIELD OF THE INVENTION

Embodiments of the present invention relate to coated medical devices,and particularly to coated balloon catheters, and their use for rapidlydelivering a therapeutic agent to particular tissue or body lumen, fortreatment of disease and particularly for reducing stenosis and latelumen loss of a body lumen. Embodiments of the present invention alsorelate to methods of manufacturing these medical devices, the drugreleasing coatings comprising at least one of an oil, a fatty acid, anda lipid provided on these medical devices, the solutions for makingthose coatings, and methods for treating a body lumen such as thevasculature, including particularly arterial vasculature, for example,using these coated medical devices.

BACKGROUND OF THE INVENTION

It has become increasingly common to treat a variety of medicalconditions by introducing a medical device into the vascular system orother lumen within a human or veterinary patient such as the esophagus,trachea, colon, biliary tract, or urinary tract. For example, medicaldevices used for the treatment of vascular disease include stents,catheters, balloon catheters, guide wires, cannulas and the like. Whilethese medical devices initially appear successful, the benefits areoften compromised by the occurrence of complications, such as latethrombosis, or recurrence of disease, such as stenosis (restenosis),after such treatment.

Restenosis, for example, involves a physiological response to thevascular injury caused by angioplasty. Over time, de-endotheliaziationand injury to smooth muscle cells results in thrombus deposition,leukocyte and macrophage infiltration, smooth muscle cellproliferation/migration, fibrosis and extracellular matrix deposition.Inflammation plays a pivotal role linking early vascular injury to theeventual consequence of neointimal growth and lumen compromise. Inballoon-injured arteries, leukocyte recruitment is confined to earlyneutrophil infiltration, while in stented arteries, early neutrophilrecruitment is followed by prolonged macrophage accumulation. Thewidespread use of coronary stents has altered the vascular response toinjury by causing a more intense and prolonged inflammatory state, dueto chronic irritation from the implanted foreign body, and in the caseof drug eluting stents (DES), from insufficient biocompatibility of thepolymer coating.

Over the past several years, numerous local drug delivery systems havebeen developed for the treatment and/or the prevention of restenosisafter balloon angioplasty or stenting. Examples include local drugdelivery catheters, delivery balloon catheters, and polymeric drugcoated stents. Given that many diseases affect a specific local site ororgan within the body, it is advantageous to preferentially treat onlythe affected area. This avoids high systemic drug levels, which mayresult in adverse side effects, and concentrates therapeutic agents inthe local area where they are needed. By treating just the diseasedtissue, the total quantity of drug used may be significantly reduced.Moreover, local drug delivery may allow for the use of certain effectivetherapeutic agents, which have previously been considered too toxic ornon-specific to use systemically.

One example of a local delivery system is a drug eluting stent (DES).The stent is coated with a polymer into which drug is impregnated. Whenthe stent is inserted into a blood vessel, the polymer degrades and thedrug is slowly released. The slow release of the drug, which takes placeover a period of weeks to months, has been reported as one of the mainadvantages of using DES. However, while slow release may be advantageousin the case where a foreign body, such as a stent, is deployed, which isa source of chronic irritation and inflammation, if a foreign body isnot implanted it is instead advantageous to rapidly deliver drug to thevascular tissue at the time of treatment to inhibit inflammation andcellular proliferation following acute injury. Thus, a considerabledisadvantage of a DES, or any other implanted medical device designedfor sustained release of a drug, is that the drug is incapable of beingrapidly released into the vessel.

Additionally, while drug-eluting stents were initially shown to be aneffective technique for reducing and preventing restenosis, recentlytheir efficacy and safety have been questioned. A life-threateningcomplication of the technology, late thrombosis, has emerged as a majorconcern. Drug eluting stents cause substantial impairment of arterialhealing, characterized by a lack of complete re-endothelialization and apersistence of fibrin when compared to bare metal stents (BMS), which isunderstood to be the underlying the cause of late DES thrombosis.Concerns have also been raised that the polymeric matrix on the stent inwhich the anti-proliferative drug is embedded might exacerbateinflammation and thrombosis, since the polymers used are notsufficiently biocompatible. These polymeric systems are designed tofacilitate long-term sustained release of drug over a period of days,months, or years, not over a period of seconds or minutes. The polymericdrug coatings of medical devices do not release the polymer, whichremains on the device even after drug is released. Even if biodegradablepolymers are used, polymer and drug are not released at the same time.Rapid release of drug, an intent of embodiments of the presentinvention, from these polymeric systems is not possible. Thus, combininga therapeutic agent with a polymer in a medical device coating may havesignificant disadvantages.

Another important limitation of the DES is that the water insolubledrugs are not evenly distributed in the polymeric matrix of the coating.Furthermore, drug and polymer are concentrated on the struts of thestent, but not in gaps between the struts. The non-uniform distributionof drug causes non-uniform drug release to the tissue of the vesselwalls. This may cause tissue damage and thrombosis in areas exposed toexcess drug and hyperplasia and restenosis areas that are undertreated.Thus, there is a need to improve the uniformity of drug delivery totarget tissues by improving drug solubility in coatings of medicaldevices by increasing the drug's compatibility with carriers in thecoatings, such as a polymeric matrix, thereby eliminating or reducingthe size of drug crystal particles in the polymeric matrix or othercoating to create a uniform drug distribution in the drug coating on themedical device.

Yet another important limitation of the DES is that only a limitedamount of an active agent can be loaded into the relatively smallsurface area of the stent.

Non-stent based local delivery systems, such as balloon catheters, havealso been effective in the treatment and prevention of restenosis. Theballoon is coated with an active agent, and when the blood vessel isdilated, the balloon is pressed against the vessel wall to deliver theactive agent. Thus, when balloon catheters are used, it is advantageousfor the drug in the coating to be rapidly released and absorbed by bloodvessel tissues. Any component of the coating that inhibits rapidrelease, such as a polymer, liposome, or encapsulating particle, isnecessarily disadvantageous to the intended use of the balloon catheter,which is inflated for a very brief period of time and then removed fromthe body.

Hydrophilic drugs, such as heparin, have been reported to be deliverableby polymeric hydrogel coated balloon catheters. However, a polymerichydrogel coating can not effectively deliver water insoluble drugs (suchas paclitaxel and rapamycin), because they can not mix with the hydrogelcoating. Even if hydrophobic drug could be incorporated successfullyinto a hydrogel matrix, drug cannot release through the crosslinkedpolymer network, which remains on the balloon.

The iodine contrast agent iopromide has been used with paclitaxel tocoat balloon catheters and has some success in treatment of restenosis.It was reported that contrast agent improves adhesion of paclitaxel tothe balloon surface. Iodinated contrast agents suffer from several wellknown disadvantages. When used for diagnostic procedures, they may havecomplication rates of 5-30%. These agents are associated with the riskof bradycardia, ventricular arrthymia, hypotension, heart block, sinusarrest, sinus tachycardia, and fibrillation. Iodine contrast agents mayalso induce renal failure, and as a result there are significant effortsto remove these contrast agents from the vascular system afterdiagnostic procedures.

Iodinated X-ray contrast agents are large hydrophilic sphericalmolecules. They are characterized by an extracellular distribution andrapid glomerular filtration and renal excretion. They are unable tocross membrane lipid bilayers to enter cells of the vasculature becausethey are large, polar, hydrophilic molecules. They are therefore notoptimally effective at carrying hydrophobic drugs such as paclitaxelinto cells, and the percent of paclitaxel reported to be taken up byvascular tissue after deployment of these devices is only 5-20%. Inaddition, the compatibility or miscibility of paclitaxel and iopromideis not good, and the integrity and uniformity of the coating is poor.Particles from the coating easily flake off and are lost duringhandling. These deficiencies adversely affect the amount and uniformityof drug delivered to target tissue. Improved coatings are thereforeneeded, coatings that not only avoid unnecessary doses of contrast, butthat also maintain integrity during handling and more effectively anduniformly deliver drug and facilitate its absorption by tissue.

Alternatively, balloon catheters are reported to have been coated withhydrophobic therapeutic agents that have been encapsulated in particlessuch as micelles, liposomes, nanoparticles or polymers. Liposomes, whichusually contain a core of aqueous solution, and micelles, which do not,have both been reported to be useful for pharmaceutical preparations ofwater-insoluble drugs for venous injection. However, for purposes of amedical device coating, all of these drug delivery formulations havesignificant disadvantages: drug loading is poor, and drug release fromthese preparations is slow.

Oils and lipids mix well with water-insoluble drugs such as paclitaxelor rapamycin, but when micelles or liposomes are then formed byinteraction with aqueous media, the particles and particle sizes arerelatively unstable, ranging in a broad particle size distribution fromseveral hundred nanometers to several microns in diameter. Severalreports suggest that the maximal concentration ratio of drug to lipidthat can be stably achieved in these particles is in the range of 0.2 to0.3; it is often less than 0.1.

Another disadvantage of oil-based liposome formulations is thedependence of drug absorption on the rate and extent of lipolysis.Lipolysis of oil-based triglycerides is difficult and dependent uponmany factors, and triglycerides must be digested and drug released inorder to be absorbed by diseased tissue. The amount of hydrophobic drugdelivered to tissues by these agents will be low, because liposomes andmicelles cannot efficiently release hydrophobic drug, which they carryaway before it can be absorbed by tissues. Micelles, liposomes, orparticles of oils and lipids are therefore not effective at rapidly andefficiently facilitating tissue uptake of drug during a very briefdevice deployment time, and no report has shown these types of coatingsto be effective.

Loading capacity of conventional micelles and liposomes is low. In theabsence of other considerations, the highest achievable drug to lipidratio is advantageous, since high lipid doses may raise concerns oftoxicitiy, and it is the drug—not the lipid—that provides thetherapeutic benefit, once it is delivered to target tissue. The ratio ofdrug to lipid in these formulations is often less than 0.1 and almostalways less than 0.2-0.3, because a significantly higher concentrationof lipid than drug is required in order for the drug to be encapsulatedin the particles, miscelles, or liposomes. Formulation stability ishighly dependent on drug-lipid interactions that are concentrationdependent. “In many studies, a maximum of 3 to 4 mol % drug (withrespect to phospholipid) possess stability of sufficient duration as tobe clinically useable. [ . . . ] 8 mol % paclitaxel liposomes may bephysically stable for 15 min or less”-Preparation and Characterizationof Taxane-Containing Liposomes. Methods Enzymol. 2005; 391:97-117, p.101-2. Several attempts to achieve drug to lipid concentration ratioshigher than 0.2-0.3 failed (for example, see PDA J Pharm Sci Technol2006 60(3):144-55). These technologies involve forming the drug/lipidparticles first and then coating medical devices with the preparedparticles. Liposomes, for example, are prepared by first mixing drug andlipid in organic solvent, then removing the organic solvent to form alipid film or cake, then hydrating with aqueous solution and sonicating.

There are several reports showing that drug release from liposomal,miscellar, or particular oil/lipid formulations occurs very slowly, inthe range of days to weeks or months. In addition, the inventor hasfound that drug release occurs far too slowly from a coating consistingessentially of just oil/lipid and lipophilic drug, because they bind toeach other and to the external surface of the medical device so tightlythat the drug cannot rapidly elute off the device during several minutesor less of deployment at the target site. This slow-releasing propertyof prior approaches to drug-oil, drug-fatty acid, and drug-lipidformulations is not desirable in embodiments of the present invention,wherein drug release takes place in the range of seconds to minutes.Thus the technology for oil, fatty acid, and/or lipid formulations needsto be improved significantly in order to be useful in the rapid drugrelease coatings for medical devices.

Drug that is encapsulated in polymeric particles may take even longer todiffuse from the coating (the reported range is months to years) andwill have further difficulty permeating target tissues rapidly.Microspheres formed with polymeric materials, such as polyesters, whenused to encapsulate water insoluble drugs, are unable to release thedrug until the polymeric material is degraded. Thus, these polymericmicrospheres are useful for sustained release of drug over a long periodof time but cannot rapidly release drug and facilitate tissue uptake.

Combining drugs and medical devices is a complicated area of technology.It involves the usual formulation challenges, such as those of oral orinjectable pharmaceuticals, together with the added challenge ofmaintaining drug adherence to the medical device until it reaches thetarget site and subsequently delivering the drug to the target tissueswith the desired release and absorption kinetics. Drug coatings ofmedical devices must also have properties such that they do not crackupon expansion and contraction of the device, for example, of a ballooncatheter or a stent. Furthermore, coatings must not impair functionalperformance such as burst pressure and compliance of balloons or theradial strength of self- or balloon-expanded stents. The coatingthickness must also be kept to a minimum, since a thick coating wouldincrease the medical device's profile and lead to poor trackability anddeliverability. These coatings generally contain almost no liquidchemicals, which typically are often used to stabilize drugs. Thus,formulations that are effective with pills or injectables might not workat all with coatings of medical device. If the drug releases from thedevice too easily, it may be lost during device delivery before it canbe deployed at the target site, or it may burst off the device duringthe initial phase of inflation and wash away before being pressed intocontact with target tissue of a body lumen wall. If the drug adheres toostrongly, the device may be withdrawn before the drug can be releasedand absorbed by tissues at the target tissues.

Thus, there is still a need to develop improved drug-oil, drug-fattyacid and drug-lipid coatings for medical devices that can be loaded witha higher concentration of therapeutic agent, drug, or other bioactivematerial and that can rapidly deliver that therapeutic agent directlyinto a localized tissue area during or following a medical procedure, soas to treat or prevent vascular and nonvascular diseases such asstenosis. The device should be able to quickly release the therapeuticagent during a brief 0.1-2 minute deployment of the device at the targetsite (not require a prolonged period of deployment), and the therapeuticagent should rapidly permeate the target tissue to treat disease, forexample, to relieve stenosis and prevent restenosis and late lumen lossof a body lumen.

There is still a need to develop improved drug-oil, drug-fatty acid, anddrug-lipid coatings for medical devices that release drug in seconds tominutes, not in days to months.

SUMMARY OF THE INVENTION

The present inventor has found that coating the exterior surface of amedical device, and particularly of a balloon catheter or a stent, forexample, with a layer comprising a lipophilic or water-insolubletherapeutic agent, an additive, and at least one of an oil, a fattyacid, and a lipid, wherein the additive comprises a hydrophilic part anda drug affinity part, wherein the drug affinity part is at least one ofa hydrophobic part, a part that has an affinity to the therapeutic agentby hydrogen bonding, and a part that has an affinity to the therapeuticagent by van der Waals interactions, facilitates rapid release of drugin seconds to minutes and solves the problems associated with priorapproaches to oil, fatty acid, and lipid coatings discussed above.Surprisingly, the present inventor has found that the at least oneadditive that has both a hydrophilic part and a drug affinity part andat least one of an oil, fatty acid, and lipid according to embodimentsof the present invention, in combination with a lipophilic orwater-insoluble therapeutic agent, forms an effective drug deliverycoating on a medical device that avoids the disadvantages ofconventional oil-based, fatty-acid-based, and lipid-based coatingformulations such as slow release, lipolysis dependence, and a very lowlimit to drug:lipid concentration ratio. Moreover, the coatingsaccording to embodiments of the present invention facilitate rapid drugelution off of the surface of the device and superior permeation of druginto tissues at a disease site to treat disease, for example, to relievestenosis and to reduce restenosis and late lumen loss of a body lumen.Thus, coatings according to embodiments of the present invention providean enhanced rate and/or extent of absorption of the hydrophobictherapeutic agent in diseased tissues of the vasculature or other bodylumen.

In embodiments of the present invention, the coated device reducesstenosis and late lumen loss of a body lumen.

In embodiments of the present invention, the additive comprises ahydrophilic part and a drug affinity part, wherein the drug affinitypart is at least one of a hydrophobic part, a part that has affinity tothe therapeutic agent by hydrogen bonding, a part that has affinity tothe therapeutic agent by charge, and a part that has affinity to thetherapeutic agent by van der Waals interactions. In embodiments of thepresent invention, the therapeutic agent is lipophilic orwater-insoluble.

In one embodiment, the present invention relates to a medical device fordelivering a therapeutic agent to a tissue for reducing stenosis andlate lumen loss of a body lumen, the device comprising a layer overlyingan exterior surface of the medical device. The device includes one of aballoon catheter, a perfusion balloon catheter, infusion catheter suchas distal perforated drug infusion tube, a perforated balloon, spaceddouble balloon, porous balloon, and weeping balloon, a cutting ballooncatheter, a scoring balloon catheter, a laser catheter, an atherectomydevice, a debulking catheter, a stent, a filter, a stent graft, acovered stent, a patch, a wire, and a valve. Further, the tissueincludes tissue of one of coronary vasculature, peripheral vasculature,cerebral vasculature, esophagus, airways, sinus, trachea, colon, biliarytract, urinary tract, prostate, and brain passages.

In one embodiment of the medical device, the layer overlying theexterior surface of the medical device comprises a therapeutic agent, anadditive, and at least one of an oil, a fatty acid, and a lipid, whereinthe additive comprises a hydrophilic part and a drug affinity part,wherein the drug affinity part is at least one of a hydrophobic part, apart that has an affinity to the therapeutic agent by hydrogen bonding,a part that has an affinity to the therapeutic agent by charge, and apart that has an affinity to the therapeutic agent by van der Waalsinteractions, wherein the additive is at least one of a surfactant and achemical compound, and wherein the chemical compound is water-soluble.

In one embodiment, the layer overlying the exterior surface of themedical device consists essentially of the therapeutic agent, theadditive, and the at least one of an oil, a fatty acid, and a lipid.

In one embodiment, the layer overlying the exterior surface of themedical device includes a therapeutic agent, an additive, and at leastone of an oil, a fatty acid, and a lipid, wherein the additive comprisesa hydrophilic part and a drug affinity part, wherein the drug affinitypart is at least one of a hydrophobic part, a part that has an affinityto the therapeutic agent by hydrogen bonding, and a part that has anaffinity to the therapeutic agent by van der Waals interactions, and thelayer does not include a polymer. In one embodiment, the additive in thelayer comprising the therapeutic agent, the additive, and the at leastone of an oil, fatty acid, and lipid, is an ionic or non-ionicsurfactant. In another embodiment, the additive is an aliphatic oraromatic surfactant. In another embodiment, the additive is the chemicalcompounds with one or more hydroxyl, amino, carbonyl, carboxyl, acid,amide, ester moieties thereof. In another embodiment, the additive is achemical compound with one or more hydroxyl, amino, carbonyl, carboxyl,acid, amide, or ester moieties with a molecular weight of less than5,000-10,000, preferably less than 1000-5,000, more preferably less than750-1,000, or most preferably less than 750. Molecular weight of theadditive is preferred to be less than that of the drug to be delivered.Small molecules can diffuse quickly, and they easily release from thesurface of the delivery balloon, carrying drug with them. They quicklydiffuse away from drug when the drug binds tissue. The molecular weightof the additives can not be too low, however, additives with molecularweight less than 80 are not desirable because they evaporate easily andare not stable components of the coating. In another embodiment, theadditive is hydroxyl ketone, hydroxyl lactone, hydroxyl acid, hydroxylester, or hydroxyl amide. In another embodiment, the additive isgluconolactone or ribonic acid lactone thereof. In yet anotherembodiment, the additive is chosen from meglumine/lactic acid,meglumine/gentisic acid, meglumine/acetic acid, lactobionic acid, Tween20/sorbitol, Tween 20/lactobionic acid, Tween 20/sugar or sugarderivatives, and N-octanoyl N-methylglucamine. In another embodiment,the additive is a vitamin or derivative thereof. In another embodiment,the additive is an amino acid or derivative thereof. In anotherembodiment, the additive is a protein or derivative thereof. In anotherembodiment, the additive is an albumin. In another embodiment, theadditive is soluble in an aqueous solvent and is soluble in an organicsolvent. In yet another embodiment, the additive is chosen from sorbitanoleate and sorbitan fatty esters.

In one embodiment, the at least one of an oil, a fatty acid, and a lipidin the layer overlying an exterior of the medical device is chosen fromsoybean oil, vegetable oil, flower oil, animal oil, marine oil,butterfat, coconut oil, palm oil, olive oil, peanut oil, fish oil,butanoic acid, hexanoic acid, octanoic acid, decanoic acid, dodecanoicacid, tetradecanoic acid, hexadecanoic acid, octadecanoic acid,octadecatrienoic acid, eicosanoic acid, eicosenoic acid,eicosatetraenoic acid, eicosapentaenoic acid, docosahexaenoic acid,tocotrienol, butyric acid, caproic acid, caprylic acid, capric acid,lauric acid, myristic acid, palmitic acid, palmitoleic acid, stearicacid, oleic acid, vaccenic acid, linoleic acid, alpha-linolenic acid,gamma-linolenic acid, behenic acid, erucic acid, lignoceric acid,natural or synthetic phospholipids, mono-, di-, or triacylglycerols,cardiolipin, phosphatidylglycerol, phosphatidic acid,phosphatidylcholine, alpha tocoferol, phosphatidylethanolamine,sphingomyelin, phosphatidylserine, phosphatidylinositol,dimyristoylphosphatidylcholine, dioleoylphosphatidylcholine,dipalmitoylphosphatidylcholine, distearoylphosphatidylcholine,phosphatidylethanolamines phosphatidylglycerols, sphingolipids,prostaglandins, gangliosides, neobee, niosomes, and derivatives thereof.

In one embodiment of the medical device, the additive in the layeroverlying an exterior surface of the medical device is at least one of asurfactant and a chemical compound. In one aspect of this embodiment,the chemical compound is chosen from amino alcohols, hydroxyl carboxylicacid, ester, and anhydrides, hydroxyl ketone, hydroxyl lactone, hydroxylester, sugar phosphate, sugar sulfate, ethyl oxide, ethyl glycols, aminoacids, peptides, proteins, sorbitan, glycerol, polyalcohol, phosphates,sulfates, organic acids, esters, salts, vitamins, combinations of aminoalcohol and organic acid, and their substituted molecules. In anotherembodiment of the medical device, the surfactant is chosen from ionic,nonionic, aliphatic, and aromatic surfactants, PEG fatty esters, PEGomega-3 fatty esters, ether, and alcohols, glycerol fatty esters,sorbitan fatty esters, PEG glyceryl fatty esters, PEG sorbitan fattyesters, sugar fatty esters, PEG sugar esters, and derivatives thereof.

In one embodiment, the additive in the layer overlying an exteriorsurface of the medical device is a mixture or combination of asurfactant and a chemical compound, wherein the chemical compound hasone or more hydroxyl, amino, carbonyl, carboxyl, acid, amide or estergroups. In one aspect of this embodiment, the surfactant is chosen fromionic, nonionic, aliphatic, and aromatic surfactants, PEG fatty esters,PEG omega-3 fatty esters, ether, and alcohols, glycerol fatty esters,sorbitan fatty esters, PEG glyceryl fatty esters, PEG sorbitan fattyesters, sugar fatty esters, PEG sugar esters, and derivatives thereof.In another aspect of this embodiment, the chemical compound having oneor more hydroxyl, amino, carbonyl, carboxyl, acid, amide or ester groupsis chosen from amino alcohols, hydroxyl carboxylic acid, ester, andanhydrides, hydroxyl ketone, hydroxyl lactone, hydroxyl ester, sugarphosphate, sugar sulfate, ethyl oxide, ethyl glycols, amino acids,peptides, proteins, sorbitan, glycerol, polyalcohol, phosphates,sulfates, organic acids, esters, salts, vitamins, combinations of aminoalcohol and organic acid, and their substituted molecules.

In one embodiment the present invention relates to a medical device fordelivering a therapeutic agent to a tissue, the device comprising alayer overlying an exterior surface of the medical device, the layercomprising a therapeutic agent, an additive, and at least one of an oil,a fatty acid, and a lipid, wherein the additive comprises a hydrophilicpart and a drug affinity part, wherein the drug affinity part is atleast one of a hydrophobic part, a part that has an affinity to theagent by charge, and a part that has an affinity to the therapeuticagent by van der Waals interactions, wherein the additive is chosen fromp-isononylphenoxypolyglycidol, PEG laurate, PEG oleate, PEG stearate,PEG glyceryl laurate, Tween 20, Tween 40, Tween 60, Tween 80, PEGglyceryl oleate, PEG glyceryl stearate, polyglyceryl laurate,polyglyceryl oleate, polyglyceryl myristate, polyglyceryl palmitate,polyglyceryl-6 laurate, plyglyceryl-6 oleate, polyglyceryl-6 myristate,polyglyceryl-6 palmitate, polyglyceryl-10 laurate, plyglyceryl-10oleate, polyglyceryl-10 myristate, polyglyceryl-10 palmitate PEGsorbitan monolaurate, PEG sorbitan monolaurate, PEG sorbitan monooleate,PEG sorbitan stearate, PEG oleyl ether, PEG laurayl ether, octoxynol,monoxynol, tyloxapol, sucrose monopalmitate, sucrose monolaurate,decanoyl-N-methylglucamide, n-decyl-β-D-glucopyranoside,n-decyl-β-D-maltopyranoside, n-dodecyl-β-D-glucopyranoside,n-dodecyl-β-D-maltoside, heptanoyl-N-methylglucamide,n-heptyl-β-D-glucopyranoside, n-heptyl-β-D-thioglucoside,n-hexyl-β-D-glucopyranoside, nonanoyl-N-methylglucamide,n-nonyl-β-D-glucopyranoside, octanoyl-N-methylglucamide,n-octyl-β-D-glucopyranoside, octyl-β-D-thioglucopyranoside; cystine,tyrosine, tryptophan, leucine, isoleucine, phenylalanine, asparagine,aspartic acid, glutamic acid, and methionine; acetic anhydride, benzoicanhydride, ascorbic acid, 2-pyrrolidone-5-carboxylic acid, sodiumpyrrolidone carboxylate, ethylenediaminetetraacetic dianhydride, maleicand anhydride, succinic anhydride, diglycolic anhydride, glutaricanhydride, acetiamine, benfotiamine, pantothenic acid; cetotiamine;cycothiamine, dexpanthenol, niacinamide, nicotinic acid, pyridoxal5-phosphate, nicotinamide ascorbate, riboflavin, riboflavin phosphate,thiamine, folic acid, menadiol diphosphate, menadione sodium bisulfite,menadoxime, vitamin B12, vitamin K5, vitamin K6, vitamin K6, and vitaminU; albumin, immunoglobulins, caseins, hemoglobins, lysozymes,immunoglobins, a-2-macroglobulin, fibronectins, vitronectins,firbinogens, lipases, benzalkonium chloride, benzethonium chloride,docecyl trimethyl ammonium bromide, sodium docecylsulfates, dialkylmethylbenzyl ammonium chloride, and dialkylesters of sodiumsulfonsuccinic acid, L-ascorbic acid and its salt, D-glucoascorbic acidand its salt, tromethamine, triethanolamine, diethanolamine, meglumine,glucamine, amine alcohols, glucoheptonic acid, glucomic acid, hydroxylketone, hydroxyl lactone, gluconolactone, glucoheptonolactone,glucooctanoic lactone, gulonic acid lactone, mannoic lactone, ribonicacid lactone, lactobionic acid, glucosamine, glutamic acid, benzylalcohol, benzoic acid, hydroxybenzoic acid, propyl 4-hydroxybenzoate,lysine acetate salt, gentisic acid, lactobionic acid, lactitol, sinapicacid, vanillic acid, vanillin, methyl paraben, propyl paraben,diethylene glycol, triethylene glycol, tetraethylene glycol, xylitol,2-ethoxyethanol, sugars, galactose, glucose, mannose, xylose, sucrose,lactose, maltose, sorbitol, cyclodextrin,(2-hydroxypropyl)-cyclodextrin, acetaminophen, ibuprofen, retinoic acid,lysine acetate, gentisic acid, catechin, catechin gallate, tiletamine,ketamine, propofol, lactic acids, acetic acid, salts of any of theforegoing organic acids and amines, polyglycidol, glycerols,multiglycerols, and mixtures of the additives, and derivatives thereof.

In another embodiment, the additive in the layer comprising thetherapeutic agent, the additive, and the at least one of an oil, a fattyacid, and a lipid, is chosen from Tyloxapol, Octoxynol, oleth, laureth,PEG-glyceryl, monolaurate, PEG-20 monolaurate, PEG 20 monooleate, PEG 20glyceryl monooleate, Nonoxynol, Nonylphenylpoly(glycidol),Octyl-betha-D-glycopyranoside, and deconoyl-N-methylglucamide.

In another embodiment, the additive in the layer comprising thetherapeutic agent, the additive, and the at least one of an oil, a fattyacid, and a lipid is chosen from benzalkonium chloride, benzethoniumchloride, docecyl trimethyl ammonium bromide, sodium docecylsulfates,dialkyl methylbenzyl ammonium chloride, and dialkylesters of sodiumsulfonsuccinic acid.

In one embodiment, the therapeutic agent in the layer comprising thetherapeutic agent, the additive, and the at least one of an oil, a fattyacid, and a lipid, is one of paclitaxel and analogues thereof, rapamycinand analogues thereof, beta-lapachone and analogues thereof, biologicalvitamin D and analogues thereof, and a mixture of these therapeuticagents. In another embodiment, the therapeutic agent is in combinationwith a second therapeutic agent, wherein the therapeutic agent is one ofpaclitaxel, rapamycin, and analogues thereof, and wherein the secondtherapeutic agent is one of beta-lapachone, biological active vitamin D,and their analogues. In one embodiment, the therapeutic agent is notwater-soluble.

In one embodiment, the additive enhances penetration and absorption ofthe therapeutic agent in tissue. In another embodiment, the additivepenetrates tissue, and the therapeutic agent is not water-soluble. Inanother embodiment, the additive enhances release of the therapeuticagent from the surface of the medical device. In another embodiment, theadditive has water and ethanol solubility of at least 1 mg/ml and thetherapeutic agent is not water-soluble.

In one embodiment, the concentration of the additive in the layer isfrom 1 to 20 μg/mm². In one embodiment, the concentration of the atleast one of an oil, a fatty acid, and a lipid in the layer is from 1 to20 μg/mm². In one embodiment, the concentration of the therapeutic agentin the layer is from 1 to 20 μg/mm². In another embodiment, theconcentration of the therapeutic agent in the layer is from 2 to 10μg/mm².

In one embodiment of the medical device, the device is capable ofdelivering the therapeutic agent to the tissue in about 0.2 to 10minutes, or preferably from about 0.1 to 2 minutes. In anotherembodiment, the device is capable of delivering the therapeutic agent tothe tissue in about 0.1 to 1 minute.

In one embodiment, the medical device comprising a layer overlying anexterior surface of the medical device further comprises an adherentlayer between the exterior surface of the medical device and the layer.In another embodiment, the device further comprises a top layeroverlying the surface of the layer to reduce loss of drug during transitthrough a body to the tissue. In one aspect of this embodiment, the toplayer comprises an additive that is less hydrophilic than the additivein the layer overlying the exterior surface of the medical device, andwherein the additive in the top layer is chosen fromp-isononylphenoxypolyglycidol, PEG laurate, Tween 20, Tween 40, Tween60, PEG oleate, PEG stearate, PEG glyceryl laurate, PEG glyceryl oleate,PEG glyceryl stearate, polyglyceryl laurate, plyglyceryl oleate,polyglyceryl myristate, polyglyceryl palmitate, polyglyceryl-6 laurate,plyglyceryl-6 oleate, polyglyceryl-6 myristate, polyglyceryl-6palmitate, polyglyceryl-10 laurate, plyglyceryl-10 oleate,polyglyceryl-10 myristate, polyglyceryl-10 palmitate PEG sorbitanmonolaurate, PEG sorbitan monolaurate, PEG sorbitan monooleate, PEGsorbitan stearate, PEG oleyl ether, PEG laurayl ether, octoxynol,monoxynol, tyloxapol, sucrose monopalmitate, sucrose monolaurate,decanoyl-N-methylglucamide, n-decyl-β-D-glucopyranoside,n-decyl-β-D-maltopyranoside, n-dodecyl-β-D-glucopyranoside,n-dodecyl-β-D-maltoside, heptanoyl-N-methylglucamide,n-heptyl-β-D-glucopyranoside, n-heptyl-β-D-thioglucoside,n-hexyl-β-D-glucopyranoside, nonanoyl-N-methylglucamide,n-noyl-β-D-glucopyranoside, octanoyl-N-methylglucamide,n-octyl-β-D-glucopyranoside, octyl-β-D-thioglucopyranoside; cystine,tyrosine, tryptophan, leucine, isoleucine, phenylalanine, asparagine,aspartic acid, glutamic acid, and methionine; acetic anhydride, benzoicanhydride, ascorbic acid, 2-pyrrolidone-5-carboxylic acid, sodiumpyrrolidone carboxylate, ethylenediaminetetraacetic dianhydride, maleicand anhydride, succinic anhydride, diglycolic anhydride, glutaricanhydride, acetiamine, benfotiamine, pantothenic acid; cetotiamine;cycothiamine, dexpanthenol, niacinamide, nicotinic acid, pyridoxal5-phosphate, nicotinamide ascorbate, riboflavin, riboflavin phosphate,thiamine, folic acid, menadiol diphosphate, menadione sodium bisulfite,menadoxime, vitamin B12, vitamin K5, vitamin K6, vitamin K6, and vitaminU; albumin, immunoglobulins, caseins, hemoglobins, lysozymes,immunoglobins, a-2-macroglobulin, fibronectins, vitronectins,firbinogens, lipases, benzalkonium chloride, benzethonium chloride,docecyl trimethyl ammonium bromide, sodium docecylsulfates, dialkylmethylbenzyl ammonium chloride, and dialkylesters of sodiumsulfonsuccinic acid, L-ascorbic acid and its salt, D-glucoascorbic acidand its salt, tromethamine, triethanolamine, diethanolamine, meglumine,glucamine, amine alcohols, glucoheptonic acid, glucomic acid, hydroxylketone, hydroxyl lactone, gluconolactone, glucoheptonolactone,glucooctanoic lactone, gulonic acid lactone, mannoic lactone, ribonicacid lactone, lactobionic acid, glucosamine, glutamic acid, benzylalcohol, benzoic acid, hydroxybenzoic acid, propyl 4-hydroxybenzoate,lysine acetate salt, gentisic acid, lactobionic acid, lactitol, sinapicacid, vanillic acid, vanillin, methyl paraben, propyl paraben, sorbitol,cyclodextrin, (2-hydroxypropyl)-cyclodextrin, acetaminophen, ibuprofen,retinoic acid, lysine acetate, gentisic acid, catechin, catechingallate, tiletamine, ketamine, propofol, lactic acids, acetic acid,salts of any of the foregoing organic acids and amines, polyglycidol,glycerols, multiglycerols, and mixtures of the additives, andderivatives thereof. In another embodiment, the medical device furthercomprises a dimethylsulfoxide solvent layer, wherein thedimethylsulfoxide solvent layer is overlying the surface of the layer.

In another embodiment of the medical device, the layer overlying theexterior surface of the medical device comprises a therapeutic agent, atleast two additives, and at least one of an oil, a fatty acid, and alipid.

In another embodiment of the medical device, the layer overlying theexterior surface of the medical device comprises a therapeutic agent, atleast two additives, and at least one of an oil, a fatty acid, and alipid, wherein each additive is soluble in polar organic solvent and issoluble in water. In one aspect of this embodiment, the polar organicsolvent is chosen from methanol, ethanol, isopropanol, acetone,dimethylformide, tetrahydrofuran, methylethyl ketone, dimethylsulfoxide,acetonitrile, ethyl acetate, and chloroform and mixtures of these polarorganic solvents with water.

In another embodiment of the medical device, the layer overlying theexterior surface of the medical device comprises a therapeutic agent, anadditive, and at least one of an oil, a fatty acid, and a lipid, whereinthe additive comprises a hydrophilic part and a drug affinity part,wherein the drug affinity part is at least one of a hydrophobic part, apart that has an affinity to the therapeutic agent by hydrogen bonding,and a part that has an affinity to the therapeutic agent by van derWaals interactions, wherein the therapeutic agent is interdispersed inthe matrix or dispersion of the additive and the at least one of an oil,a lipid, and a fatty acid, and wherein the therapeutic agent is notwater-soluble and is not enclosed in micelles or liposomes orencapsulated in polymer particles.

In another embodiment of the medical device, the layer overlying theexterior surface of the medical device comprises a therapeutic agent, anadditive, and at least one of an oil, a fatty acid, and a lipid, whereinthe at least one of an oil, a fatty acid, and a lipid has a fatty chainthat directly inserts into lipid membrane structures of tissue, whereinthe additive comprises a hydrophilic part and a drug affinity part,wherein the additive has one or more functional groups which haveaffinity to the drug by hydrogen bonding and/or van der Waalsinteractions (the functional groups include hydroxyl, ester, amide,carboxylic acid, primary, second, and tertiary amine, carbonyl,anhydrides, oxides, and amino alcohols), wherein the therapeutic agentis not water-soluble and is not enclosed in micelles or liposomes orencapsulated in particles, and wherein the layer does not includepolymer.

In another embodiment, the present invention relates to a ballooncatheter for delivering a therapeutic agent to a blood vessel forreducing stenosis, the catheter comprising a coating layer overlying anexterior surface of a balloon. In one embodiment of the ballooncatheter, the coating layer comprises a therapeutic agent, an additive,and at least one of an oil, a fatty acid, and a lipid, wherein theadditive comprises a hydrophilic part and a drug affinity part, whereinthe drug affinity part is at least one of a hydrophobic part, a partthat has an affinity to the therapeutic agent by hydrogen bonding, apart that has an affinity to the therapeutic agent by charge, and a parthat has an affinity to the therapeutic agent by van der Waalsinteractions, wherein the additive is at least one of a surfactant and achemical compound, and wherein the chemical compound is water-soluble.In one embodiment, the therapeutic agent is not enclosed in micelles orliposomes or encapsulated in polymer particles.

In one embodiment of the balloon catheter, the additive in the coatinglayer is an ionic or non-ionic surfactant. In another embodiment, theadditive is a vitamin or derivative thereof. In another embodiment, theadditive is an amino acid or derivative thereof. In another embodiment,the additive is a protein or derivative thereof. In another embodiment,the additive is an albumin. In another embodiment, the additive issoluble in an aqueous solvent and is soluble in an organic solvent. Inanother embodiment, the additive is an organic acid or an anhydridethereof. In yet another embodiment, the additive is chosen from sorbitanoleate and sorbitan fatty esters.

In one embodiment, the additive in the coating layer comprising thetherapeutic agent, the additive, and the at least one of an oil, a fattyacid, and a lipid is chosen from PEG fatty esters, PEG omega-3 fattyesters and alcohols, glycerol fatty esters, sorbitan fatty esters, PEGglyceryl fatty esters, PEG sorbitan fatty esters, sugar fatty esters,PEG sugar esters, vitamins and derivatives, amino acids, multi aminoacids and derivatives, peptides, polypeptides, proteins, quaternaryammonium salts, organic acids, salts and anhydrides.

In another embodiment, the additive in the coating layer comprising thetherapeutic agent, the additive, and the at least one of an oil, a fattyacid, and a lipid is chosen from p-isononylphenoxypolyglycidol, PEGlaurate, Tween 20, Tween 40, Tween 60, Tween 80, PEG oleate, PEGstearate, PEG glyceryl laurate, PEG glyceryl oleate, PEG glycerylstearate, polyglyceryl laurate, plyglyceryl oleate, polyglycerylmyristate, polyglyceryl palmitate, polyglyceryl-6 laurate, plyglyceryl-6oleate, polyglyceryl-6 myristate, polyglyceryl-6 palmitate,polyglyceryl-10 laurate, plyglyceryl-10 oleate, polyglyceryl-10myristate, polyglyceryl-10 palmitate PEG sorbitan monolaurate, PEGsorbitan monolaurate, PEG sorbitan monooleate, PEG sorbitan stearate,PEG oleyl ether, PEG laurayl ether, octoxynol, monoxynol, tyloxapol,sucrose monopalmitate, sucrose monolaurate, decanoyl-N-methylglucamide,n-decyl-β-D-glucopyranoside, n-decyl-β-D-maltopyranoside,n-dodecyl-β-D-glucopyranoside, n-dodecyl-β-D-maltoside,heptanoyl-N-methylglucamide, n-heptyl-β-D-glucopyranoside,n-heptyl-β-D-thioglucoside, n-hexyl-β-D-glucopyranoside,nonanoyl-N-methylglucamide, n-noyl-β-D-glucopyranoside,octanoyl-N-methylglucamide, n-octyl-β-D-glucopyranoside,octyl-β-D-thioglucopyranoside; cystine, tyrosine, tryptophan, leucine,isoleucine, phenylalanine, asparagine, aspartic acid, glutamic acid, andmethionine; acetic anhydride, benzoic anhydride, ascorbic acid,2-pyrrolidone-5-carboxylic acid, sodium pyrrolidone carboxylate,ethylenediaminetetraacetic dianhydride, maleic and anhydride, succinicanhydride, diglycolic anhydride, glutaric anhydride, acetiamine,benfotiamine, pantothenic acid; cetotiamine; cycothiamine, dexpanthenol,niacinamide, nicotinic acid, pyridoxal 5-phosphate, nicotinamideascorbate, riboflavin, riboflavin phosphate, thiamine, folic acid,menadiol diphosphate, menadione sodium bisulfite, menadoxime, vitaminB12, vitamin K5, vitamin K6, vitamin K6, and vitamin U; albumin,immunoglobulins, caseins, hemoglobins, lysozymes, immunoglobins,a-2-macroglobulin, fibronectins, vitronectins, firbinogens, lipases,benzalkonium chloride, benzethonium chloride, docecyl trimethyl ammoniumbromide, sodium docecylsulfates, dialkyl methylbenzyl ammonium chloride,and dialkylesters of sodium sulfonsuccinic acid, L-ascorbic acid and itssalt, D-glucoascorbic acid and its salt, tromethamine, triethanolamine,diethanolamine, meglumine, glucamine, amine alcohols, glucoheptonicacid, glucomic acid, hydroxyl ketone, hydroxyl lactone, gluconolactone,glucoheptonolactone, glucooctanoic lactone, gulonic acid lactone,mannoic lactone, ribonic acid lactone, lactobionic acid, glucosamine,glutamic acid, benzyl alcohol, benzoic acid, hydroxybenzoic acid, propyl4-hydroxybenzoate, lysine acetate salt, gentisic acid, lactobionic acid,lactitol, sinapic acid, vanillic acid, vanillin, methyl paraben, propylparaben, diethylene glycol, triethylene glycol, tetraethylene glycol,xylitol, 2-ethoxyethanol, sugars, galactose, glucose, mannose, xylose,sucrose, lactose, maltose, sorbitol, cyclodextrin,(2-hydroxypropyl)-cyclodextrin, acetaminophen, ibuprofen, retinoic acid,lysine acetate, gentisic acid, catechin, catechin gallate, tiletamine,ketamine, propofol, lactic acids, acetic acid, salts of any of theforegoing organic acids and amines, polyglycidol, glycerols,multiglycerols, and mixtures of the additives, and derivatives thereof.

In another embodiment, the additive in the coating layer comprising thetherapeutic agent, the additive, and the at least one of an oil, a fattyacid and a lipid is chosen from Tyloxapol, Octoxynol, oleth, laureth,PEG-glyceryl, monolaurate, PEG-20 monolaurate, PEG 20 monooleate, PEG 20glyceryl monooleate, Nonoxynol, Nonylphenylpoly(glycidol),Octyl-betha-D-glycopyranoside, and deconoyl-N-methylglucamide.

In another embodiment, the additive in the coating layer comprising thetherapeutic agent, the additive, and the at least one of an oil, a fattyacid, and a lipid is chosen from benzalkonium chloride, benzethoniumchloride, docecyl trimethyl ammonium bromide, sodium docecylsulfates,dialkyl methylbenzyl ammonium chloride, and dialkylesters of sodiumsulfonsuccinic acid.

In one embodiment, the therapeutic agent is one of paclitaxel andanalogues thereof, rapamycin and analogues thereof, beta-lapachone andanalogues thereof, biological vitamin D and analogues thereof, and amixture of these therapeutic agents. In another embodiment, thetherapeutic agent is in combination with a second therapeutic agent,wherein the therapeutic agent is one of paclitaxel, rapamycin, andanalogues thereof, and wherein the second therapeutic agent is one ofbeta-lapachone, biological active vitamin D, and their analogues. In oneembodiment, the therapeutic agent is not water-soluble.

In one embodiment, the additive enhances penetration and absorption ofthe therapeutic agent in the blood vessel. In another embodiment, theadditive penetrates the blood vessel, and the therapeutic agent is notwater-soluble. In another embodiment, the additive has water and ethanolsolubility of at least 1 mg/ml, and the therapeutic agent is notwater-soluble.

In one embodiment of the balloon catheter, the catheter furthercomprises an adherent layer between the exterior surface of the balloonand the coating layer. In another embodiment, the catheter furthercomprises a top layer overlying the coating layer, wherein the top layerreduces loss of the therapeutic agent during transit through a body tothe blood vessel. In one embodiment, the top layer comprises an additivechosen from those additives, according to embodiments of the inventiondescribed herein. The top layer will be slowly dissolved during transitthrough a body to the body lumen to the target site for therapeuticintervention. This top layer will reduce drug loss during transit andincrease the drug available to the tissue when the medical device ofembodiments of the present invention is pressed into contact withluminal tissue. In one embodiment, the additive in the top layer is lesshydrophilic than the additive in the coating layer. In anotherembodiment, the catheter further comprises a dimethylsulfoxide solventlayer, wherein the dimethylsulfoxide solvent layer is overlying thesurface of the coating layer.

In one embodiment, the balloon catheter is capable of delivering thetherapeutic agent to the blood vessel in about 0.2 to 2 minutes. Inanother embodiment, the balloon catheter is capable of delivering thetherapeutic agent to the blood vessel in about 0.1 to 1 minute.

In one embodiment of the balloon catheter, the concentration of thetherapeutic agent in the coating layer is from 1 to 20 μg/mm². Inanother embodiment, the concentration of the therapeutic agent in thecoating layer is from 2 to 6 μg/mm². In one embodiment, theconcentration of the additive in the coating layer is from 1 to 10μg/mm².

In yet a further embodiment, the present invention relates to a ballooncatheter for delivering a therapeutic agent to a blood vessel. In oneaspect of this embodiment, the catheter comprises an elongate memberhaving a lumen and a distal end, an expandable balloon attached to thedistal end of the elongate member and in fluid communication with thelumen, and a coating layer overlying an exterior surface of the balloon.In one aspect of this embodiment, the coating layer overlying thesurface of the balloon comprises a lipophilic or water-insolubletherapeutic agent, an additive, and at least one of an oil, a fattyacid, and a lipid wherein the additive comprises a hydrophilic part anda drug affinity part, wherein the drug affinity part is at least one ofa hydrophobic part, a part that has an affinity to the therapeutic agentby hydrogen bonding, a part that has an affinity to the therapeuticagent by charge, and a part that has an affinity to the therapeuticagent by van der Waals interactions, wherein the additive iswater-soluble, and wherein the catheter is capable of delivering thetherapeutic agent to the blood vessel in less than about 2 minutes.

In one embodiment, the coating layer overlying the surface of theballoon consists essentially of the therapeutic agent, the additive, andthe at least one of an oil, a fatty acid, and a lipid. In oneembodiment, the therapeutic agent in the coating layer overlying thesurface of the balloon is paclitaxel and analogues thereof. In anotherembodiment, the therapeutic agent in the coating layer overlying thesurface of the balloon is rapamycin and analogues thereof.

In one embodiment, the concentration of the therapeutic agent in thecoating layer is from 2.5 to 6 μg/mm².

In one embodiment, the additive in the coating layer overlying thesurface of the balloon is an ionic or non-ionic surfactant. In anotherembodiment, the additive in the coating layer overlying the surface ofthe balloon is a vitamin or derivative thereof.

In one embodiment, the additive in the coating layer overlying thesurface of the balloon is chosen from Tyloxapol, Octoxynol, oleth,laureth, PEG-glyceryl, monolaurate, PEG-20 monolaurate, PEG 20monooleate, PEG 20 glyceryl monooleate, Nonoxynol,Nonylphenylpoly(glycidol), Octyl-betha-D-glycopyranoside, anddeconoyl-N-methylglucamide. In another embodiment, the additive in thecoating layer overlying the surface of the balloon is chosen from PEGfatty esters, PEG omega-3 fatty esters and alcohols, glycerol fattyesters, sorbitan fatty esters, PEG glyceryl fatty esters, PEG sorbitanfatty esters, sugar fatty esters, PEG sugar esters, vitamins andderivatives, amino acids, multi amino acids and derivatives, peptides,polypeptides, proteins, quaternary ammonium salts, organic acids, saltsand anhydrides.

In another embodiment, the additive in the coating layer overlying thesurface of the balloon is chosen from p-isononylphenoxypolyglycidol, PEGlaurate, PEG oleate, PEG stearate, PEG glyceryl laurate, PEG glyceryloleate, PEG glyceryl stearate, polyglyceryl laurate, plyglyceryl oleate,polyglyceryl myristate, polyglyceryl palmitate, polyglyceryl-6 laurate,plyglyceryl-6 oleate, polyglyceryl-6 myristate, polyglyceryl-6palmitate, polyglyceryl-10 laurate, plyglyceryl-10 oleate,polyglyceryl-10 myristate, polyglyceryl-10 palmitate PEG sorbitanmonolaurate, PEG sorbitan monolaurate, PEG sorbitan monooleate, PEGsorbitan stearate, PEG oleyl ether, PEG laurayl ether, octoxynol,monoxynol, tyloxapol, sucrose monopalmitate, sucrose monolaurate, Tween20, Tween 40, Tween 60, decanoyl-N-methylglucamide,n-decyl-β-D-glucopyranoside, n-decyl-β-D-maltopyranoside,n-dodecyl-β-D-glucopyranoside, n-dodecyl-β-D-maltoside,heptanoyl-N-methylglucamide, n-heptyl-β-D-glucopyranoside,n-heptyl-β-D-thioglucoside, n-hexyl-β-D-glucopyranoside,nonanoyl-N-methylglucamide, n-noyl-β-D-glucopyranoside,octanoyl-N-methylglucamide, n-octyl-β-D-glucopyranoside,octyl-β-D-thioglucopyranoside; cystine, tyrosine, tryptophan, leucine,isoleucine, phenylalanine, asparagine, aspartic acid, glutamic acid, andmethionine (amino acids); acetic anhydride, benzoic anhydride, ascorbicacid, 2-pyrrolidone-5-carboxylic acid, sodium pyrrolidone carboxylate,ethylenediaminetetraacetic dianhydride, maleic and anhydride, succinicanhydride, diglycolic anhydride, glutaric anhydride, acetiamine,benfotiamine, pantothenic acid (organic acids and anhydrides);cetotiamine; cycothiamine, dexpanthenol, niacinamide, nicotinic acid,pyridoxal 5-phosphate, nicotinamide ascorbate, riboflavin, riboflavinphosphate, thiamine, folic acid, menadiol diphosphate, menadione sodiumbisulfite, menadoxime, vitamin B12, vitamin K5, vitamin K6, vitamin K6,and vitamin U (vitamins); albumin, immunoglobulins, caseins,hemoglobins, lysozymes, immunoglobins, a-2-macroglobulin, fibronectins,vitronectins, firbinogens, lipases, benzalkonium chloride, benzethoniumchloride, docecyl trimethyl ammonium bromide, sodium docecylsulfates,dialkyl methylbenzyl ammonium chloride, and dialkylesters of sodiumsulfonsuccinic acid (ionic surfactants), L-ascorbic acid and its salt,D-glucoascorbic acid and its salt, triethanolamine, diethanolamine,meglumine, tromethamine, glucamine, glucosamine, glucoheptonic acid,glucomic acid, hydroxyl ketone, hydroxyl lactone, gluconolactone,glucoheptonolactone, glucooctanoic lactone, gulonic acid lactone,mannoic lactone, ribonic acid lactone, lactobionic acid, glucosamine,glutamic acid, benzyl alcohol, benzoic acid, hydroxybenzoic acid,vanillin, vanillic acid, vanillic acid diethylamide, lysine acetatesalt, gentisic acid, lactobionic acid, lactitol, sorbitol, cyclodextrin,(2-hydroxypropyl)-cyclodextrin, acetaminophen, ibuprofen, catechin,catechin gallate, methyl paraben, ethyl paraben, propyl paraben, butylparaben, tiletamine, ketamine, propofol, lactic acids, acetic acid,diethylene glycol, triethylene glycol, tetraethylene glycol, xylitol,2-ethoxyethanol, sugars, galactose, glucose, mannose, xylose, sucrose,lactose, maltose, salts of any organic acid and amine described above,polyglycidol, glycerols and multiglycerols (chemical compounds with oneor more hydroxyl, amino, carbonyl, carboxyl, or ester moieties). In yetanother embodiment, the additive in the coating layer overlying thesurface of the balloon is chosen from benzalkonium chloride,benzethonium chloride, docecyl trimethyl ammonium bromide, sodiumdocecylsulfates, dialkyl methylbenzyl ammonium chloride, anddialkylesters of sodium sulfonsuccinic acid.

In one embodiment, the balloon catheter further comprises adimethylsulfoxide solvent layer overlying the coating layer, wherein thedimethylsulfoxide layer enhances the ability of the therapeutic agent topenetrate into the blood vessel. In another embodiment, the ballooncatheter further comprises an adherent layer between the exteriorsurface of the balloon and the coating layer. In yet another embodiment,the balloon catheter further comprises a top layer overlying the coatinglayer, wherein the top layer reduces loss of the therapeutic agentand/or additive in the coating layer during transit through a body orblood vessel to the target site for intervention.

In yet a further embodiment, the present invention relates to apharmaceutical composition for treating a diseased body lumen or cavityafter a surgical or interventional procedure, wherein the compositioncomprises a therapeutic agent, an additive, and at least one of an oil,a fatty acid, and a lipid, wherein the additive comprises a hydrophilicpart and a drug affinity part, wherein the drug affinity part is atleast one of a hydrophobic part, a part that has an affinity to thetherapeutic agent by hydrogen bonding, and a part that has an affinityto the therapeutic agent by van der Waals interactions, and wherein thetherapeutic agent is not enclosed in micelles or liposomes orencapsulated in polymer particles.

In yet a further embodiment, the present invention relates to a methodfor treating a diseased body lumen or cavity after a surgical orinterventional procedure comprising delivering a pharmaceuticalcomposition at a surgical site by injection or spraying with a catheter,wherein the composition comprises a therapeutic agent, an additive, andat least one of an oil, a fatty acid and a lipid, wherein the additivecomprises a hydrophilic part and a drug affinity part, wherein the drugaffinity part is at least one of a hydrophobic part, a part that has anaffinity to the therapeutic agent by hydrogen bonding, and a part thathas an affinity to the therapeutic agent by van der Waals interactions,and wherein the therapeutic agent is not enclosed in micelles orliposomes or encapsulated in polymer particles.

In yet a further embodiment, the present invention relates to apharmaceutical composition for treating a cancer including cancers ofthe ovary, breast, lung, esophagus, head and neck region, bladder,brain, liver, colon and lymphomas, wherein the composition comprises atherapeutic agent, an additive, and at least one of an oil, a fatty acidand a lipid, wherein the additive comprises a hydrophilic part and adrug affinity part, wherein the drug affinity part is at least one of ahydrophobic part, a part that has an affinity to the therapeutic agentby hydrogen bonding, and a part that has an affinity to the therapeuticagent by van der Waals interactions, and wherein the therapeutic agentis not enclosed in micelles or liposomes or encapsulated in polymerparticles. In one aspect of this embodiment, the therapeutic agent ischosen from paclitaxel and analogues thereof and rapamycin and analoguesthereof.

In yet a further embodiment, the present invention relates to a solutionfor coating a medical device. In one aspect of this embodiment, thesolution comprises an organic solvent, a therapeutic agent, an additive,and at least one of an oil, a fatty acid, and a lipid, wherein theadditive comprises a hydrophilic part and a drug affinity part, whereinthe drug affinity part is at least one of a hydrophobic part, a partthat has an affinity to the therapeutic agent by hydrogen bonding, and apart that has an affinity to the therapeutic agent by van der Waalsinteractions, and wherein the therapeutic agent is not enclosed inmicelles or liposomes or encapsulated in polymer particles. In anotherembodiment, the solution for coating a medical device does not include apolymer.

In one embodiment, the additive in the coating solution is an ionic ornon-ionic surfactant. In another embodiment, the additive in the coatingsolution is a vitamin or derivative thereof.

In one embodiment, the additive in the coating solution is chosen fromTyloxapol, Octoxynol, oleth, laureth, PEG-glyceryl, monolaurate, PEG-20monolaurate, PEG 20 monooleate, PEG 20 glyceryl monooleate, Nonoxynol,Nonylphenylpoly(glycidol), Octyl-betha-D-glycopyranoside, anddeconoyl-N-methylglucamide.

In another embodiment, the additive in the coating solution is chosenfrom PEG fatty esters, PEG omega-3 fatty esters and alcohols, glycerolfatty esters, sorbitan fatty esters, PEG glyceryl fatty esters, PEGsorbitan fatty esters, sugar fatty esters, PEG sugar esters, vitaminsand derivatives, amino acids, multi amino acids and derivatives,peptides, polypeptides, proteins, quaternary ammonium salts, organicacids, salts and anhydrides.

In another embodiment, the additive in the coating solution is chosenfrom p-isononylphenoxypolyglycidol, PEG laurate, PEG oleate, PEGstearate, PEG glyceryl laurate, PEG glyceryl oleate, PEG glycerylstearate, polyglyceryl laurate, plyglyceryl oleate, polyglycerylmyristate, polyglyceryl palmitate, polyglyceryl-6 laurate, plyglyceryl-6oleate, polyglyceryl-6 myristate, polyglyceryl-6 palmitate,polyglyceryl-10 laurate, plyglyceryl-10 oleate, polyglyceryl-10myristate, polyglyceryl-10 palmitate PEG sorbitan monolaurate, PEGsorbitan monolaurate, PEG sorbitan monooleate, PEG sorbitan stearate,PEG oleyl ether, PEG laurayl ether, octoxynol, monoxynol, tyloxapol,Tween 20, Tween 80, Tween 40, Tween 60, sucrose monopalmitate, sucrosemonolaurate, decanoyl-N-methylglucamide, n-decyl-β-D-glucopyranoside,n-decyl-β-D-maltopyranoside, n-dodecyl-β-D-glucopyranoside,n-dodecyl-β-D-maltoside, heptanoyl-N-methylglucamide,n-heptyl-β-D-glucopyranoside, n-heptyl-β-D-thioglucoside,n-hexyl-β-D-glucopyranoside, nonanoyl-N-methylglucamide,n-noyl-β-D-glucopyranoside, octanoyl-N-methylglucamide,n-octyl-β-D-glucopyranoside, octyl-β-D-thioglucopyranoside; cystine,tyrosine, tryptophan, leucine, isoleucine, phenylalanine, asparagine,aspartic acid, glutamic acid, and methionine (amino acids); aceticanhydride, benzoic anhydride, ascorbic acid, 2-pyrrolidone-5-carboxylicacid, sodium pyrrolidone carboxylate, ethylenediaminetetraaceticdianhydride, maleic and anhydride, succinic anhydride, diglycolicanhydride, glutaric anhydride, acetiamine, benfotiamine, pantothenicacid (organic acids and anhydrides); cetotiamine; cycothiamine,dexpanthenol, niacinamide, nicotinic acid, pyridoxal 5-phosphate,nicotinamide ascorbate, riboflavin, riboflavin phosphate, thiamine,folic acid, menadiol diphosphate, menadione sodium bisulfite,menadoxime, vitamin B12, vitamin K5, vitamin K6, vitamin K6, and vitaminU (vitamins); albumin, immunoglobulins, caseins, hemoglobins, lysozymes,immunoglobins, a-2-macroglobulin, fibronectins, vitronectins,firbinogens, lipases (proteins), benzalkonium chloride, benzethoniumchloride, docecyl trimethyl ammonium bromide, sodium docecylsulfates,dialkyl methylbenzyl ammonium chloride, and dialkylesters of sodiumsulfonsuccinic acid (ionic surfactants), L-ascorbic acid and its salt,D-glucoascorbic acid and its salt, triethanolamine, diethanolamine,meglumine, tromethamine, glucamine, glucosamine, glucoheptonic acid,glucomic acid, hydroxyl ketone, hydroxyl lactone, gluconolactone,glucoheptonolactone, glucooctanoic lactone, gulonic acid lactone,mannoic lactone, ribonic acid lactone, lactobionic acid, glutamic acid,benzyl alcohol, benzoic acid, hydroxybenzoic acid, vanillin, vanillicacid, vanillic acid diethylamide, lysine acetate salt, gentisic acid,lactobionic acid, lactitol, diethylene glycol, triethylene glycol,tetraethylene glycol, xylitol, 2-ethoxyethanol, sugars, galactose,glucose, mannose, xylose, sucrose, lactose, maltose, sorbitol,cyclodextrin, (2-hydroxypropyl)-cyclodextrin, acetaminophen, ibuprofen,catechin, catechin gallate, methyl paraben, ethyl paraben, propylparaben, butyl paraben, tiletamine, ketamine, propofol, lactic acids,acetic acid, salts of any organic acid and amine described above(chemical compounds with one or more hydroxyl, amino, carbonyl,carboxyl, or ester moieties).

In another embodiment, the additive in the solution is chosen fromsorbitan fatty esters. In yet another embodiment, the additive in thecoating solution is chosen from benzalkonium chloride, benzethoniumchloride, docecyl trimethyl ammonium bromide, sodium docecylsulfates,dialkyl methylbenzyl ammonium chloride, and dialkylesters of sodiumsulfonsuccinic acid.

In one embodiment, the therapeutic agent in the coating solution ispaclitaxel or rapamycin.

In one embodiment, the content of the therapeutic agent in the solutionis from 0.5-50% by weight. In one embodiment, the content of theadditive in the coating solution is from 1-45% by weight.

In one embodiment, the additive in the solution is soluble in aqueoussolvent and is soluble in organic solvent.

In yet a further embodiment, the present invention relates to a medicaldevice for delivering a therapeutic agent to a tissue, the devicecomprising a first layer applied to an exterior surface of the medicaldevice, and a second layer overlying the first layer. In one aspect ofthis embodiment, the first layer comprises a therapeutic agent, and thesecond layer comprises a mixture of the additive and at least one of anoil, a fatty acid, and a lipid, and wherein the therapeutic agent in thefirst layer is not enclosed in micelles or liposomes or encapsulated inpolymer particles. In one aspect of this embodiment, the first layerfurther comprises an additive and at least one of an oil, a fatty acid,and a lipid. In another aspect of this embodiment, the second layerfurther comprises a therapeutic agent. In yet a further aspect of thisembodiment, the first layer further comprises an additive, at least oneof an oil, a fatty acid, and a lipid, and the second layer furthercomprises a therapeutic agent.

In a further embodiment, the present invention relates to a two layercoating comprising a first layer comprising a therapeutic agent, and asecond layer comprising an additive and at least one of an oil, a fattyacid, and a lipid. In one aspect of this embodiment, the second layermay be overlying the first layer. In one aspect of this embodiment, theadditive in the second layer is hydrophilic, and the therapeutic agentin the first layer is not enclosed in micelles or liposomes orencapsulated in polymer particles. In one aspect of this embodiment, thefirst layer further comprises an additive and at least one of an oil, afatty acid, and a lipid. In another aspect of this embodiment, thesecond layer further comprises a therapeutic agent. In yet anotheraspect of this embodiment, the first layer further comprises an additiveand at least one of an oil, a fatty acid, and a lipid and the secondlayer further comprises a therapeutic agent.

In a further embodiment, the present invention relates to a method forpreparing a medical device. In one aspect of this embodiment, the methodcomprises (a) preparing a coating solution comprising an organicsolvent, a therapeutic agent, an additive, and at least one of an oil, afatty acid, and a lipid, wherein the additive comprises a hydrophilicpart and a drug affinity part, wherein the drug affinity part is atleast one of a hydrophobic part, a part that has an affinity to thetherapeutic agent by hydrogen bonding, and a part that has an affinityto the therapeutic agent by van der Waals interactions, and wherein thetherapeutic agent is not enclosed in micelles or liposomes orencapsulated in polymer particles, (b) applying the coating solution toa medical device, and (c) drying the coating solution, forming a coatinglayer. In one aspect of this embodiment, the coating is applied bydipping a portion of the exterior surface of the medical device in thecoating solution. In another aspect of this embodiment, the coating isapplied by spraying a portion of the exterior surface of the medicaldevice with a coating solution. In another aspect of this embodiment,steps (b) and (c) are repeated until a therapeutically effective amountof the therapeutic agent in the coating layer is deposited on thesurface of the medical device. In another aspect of this embodiment, thetotal thickness of the coating layer is from about 0.1 to 200 microns.In another aspect of this embodiment, the concentration density of theat least one therapeutic agent applied to the surface of the medicaldevice is from about 1 to 20 μg/mm², or in another aspect from about 2to 6 μg/mm². In yet another aspect of this embodiment, the methodfurther comprises applying a dimethylsulfoxide solvent to the driedcoating layer obtained in step (c).

In a further embodiment, the present invention relates to a method forpreparing a drug coated balloon catheter. In one aspect of thisembodiment, the method comprises, (a) preparing a coating solutioncomprising an organic solvent, a therapeutic agent, an additive, and atleast one of an oil, a fatty acid, and a lipid, wherein the additivecomprises a hydrophilic part and a drug affinity part, wherein the drugaffinity part is at least one of a hydrophobic part, a part that has anaffinity to the therapeutic agent by hydrogen bonding, and a part thathas an affinity to the therapeutic agent by van der Waals interactions,(b) applying the coating solution to an inflated balloon catheter, and(c) deflating and folding the balloon catheter and drying the coatingsolution to increase uniformity of drug coating.

In a further embodiment, the present invention relates to a method fortreating a blood vessel. In one aspect of this embodiment, the methodcomprises inserting a medical device comprising a coating layer into theblood vessel, wherein the coating layer comprises a therapeutic agent,an additive, and at least one of an oil, a fatty acid, and a lipid,wherein the additive comprises a hydrophilic part and a drug affinitypart, wherein the drug affinity part is at least one of a hydrophobicpart, a part that has an affinity to the therapeutic agent by hydrogenbonding, and a part that has an affinity to the therapeutic agent by vander Waals interactions, and wherein the therapeutic agent is notenclosed in micelles or liposomes or encapsulated in polymer particles,and releasing the therapeutic agent into the tissue of the blood vesselin 2 minutes or less.

In a further embodiment, the present invention relates to a method fortreating a total occlusion or narrowing of body passages. In one aspectof this embodiment, the method comprises removing plaques in the bodypassages, for example, by one of a debulking catheter, a laseratherectomy, a directing atherectomy, or a rotational atherectomy,inserting a medical device comprising a coating layer into the bodypassages, wherein the coating layer comprises a therapeutic agent, anadditive, and at least one of an oil, a fatty acid, and a lipid, whereinthe additive comprises a hydrophilic part and a drug affinity part,wherein the drug affinity part is at least one of a hydrophobic part, apart that has an affinity to the therapeutic agent by hydrogen bonding,and a part that has an affinity to the therapeutic agent by van derWaals interactions, and releasing the therapeutic agent into the tissueof the body passage or lumen, such as a blood vessel, in 2 minutes orless.

In a further embodiment, the present invention relates to a method fortreating tissue of a body comprising bringing a medical devicecomprising a coating layer into contact with tissue of the body, whereinthe coating layer comprises a therapeutic agent, an additive, and atleast one of an oil, a fatty acid, and a lipid, wherein the additivecomprises a hydrophilic part and a drug affinity part, wherein the drugaffinity part is at least one of a hydrophobic part, a part that has anaffinity to the therapeutic agent by hydrogen bonding, and a part thathas an affinity to the therapeutic agent by van der Waals interactions,and releasing the therapeutic agent into the tissue in 2 minutes orless. In one aspect of this embodiment, the tissue includes tissue ofone of coronary vasculature, peripheral vasculature, cerebralvasculature, esophagus, airways, sinus, trachea, colon, biliary tract,urinary tract, prostate, and brain passages.

In yet a further embodiment, the present invention relates to a processof producing a balloon catheter. In one aspect of this embodiment, theprocess comprises preparing a solution comprising an organic solvent, atherapeutic agent, an additive, and at least one of an oil, a fattyacid, and a lipid, wherein the additive comprises a hydrophilic part anda drug affinity part, wherein the drug affinity part is at least one ofa hydrophobic part, a part that has an affinity to the therapeutic agentby hydrogen bonding, and a part that has an affinity to the therapeuticagent by van der Waals interactions, and wherein the therapeutic agentis not enclosed in micelles or liposomes or encapsulated in polymerparticles, applying the solution to the balloon catheter, andevaporating the solvent.

In yet a further embodiment, the present invention relates to a medicaldevice comprising a layer overlying an exterior surface of the medicaldevice, the layer comprising a therapeutic agent, an additive, and atleast one of an oil, a fatty acid and a lipid, wherein the additive isone of PEG fatty ester, PEG fatty ether, and PEG fatty alcohols. In oneaspect of this embodiment, the additive is chosen from PEG-8 laurate,PEG-8 oleate, PEG-8 stearate, PEG-9 oleate, PEG-10 laurate, PEG-10oleate, PEG-12 laurate, PEG-12 oleate, PEG-15 oleate, PEG-20 laurate,PEG-20 oleate, PEG-20 dilaurate, PEG-20 dioleate, PEG-20 distearate,PEG-32 dilaurate and PEG-32 dioleate. In another aspect of thisembodiment, the tissue includes tissue of one of coronary vasculature,peripheral vasculature, cerebral vasculature, esophagus, airways, sinus,trachea, colon, biliary tract, urinary tract, prostate, and brainpassages. In yet another aspect of this embodiment, the device includesone of a balloon catheter, a perfusion balloon catheter, a cuttingballoon catheter, a scoring balloon catheter, a laser catheter, anatherectomy device, a debulking catheter, a stent, a filter, a stentgraft, a covered stent, a patch, a wire, and a valve.

In yet a further embodiment, the present invention relates to a medicaldevice comprising a layer overlying an exterior surface of the medicaldevice, the layer comprising a therapeutic agent, an additive, and atleast one of an oil, a fatty acid, and a lipid, wherein the additive isone of glycerol and polyglycerol fatty esters and PEG glycerol fattyesters. In one aspect of this embodiment, the additive is chosen frompolyglyceryl oleate, polyglyceryl-2 dioleate, polyglyceryl-10 trioleate,polyglyceryl stearate, polyglyceryl laurate, polyglyceryl myristate,polyglyceryl palmitate, polyglyceryl linoleate, polyglyceryl-10 laurate,polyglyceryl-10 oleate, polyglyceryl-10 mono, dioleate, polyglyceryl-10stearate, polyglyceryl-10 laurate, polyglyceryl-10 myristate,polyglyceryl-10 palmitate, polyglyceryl-10 linoleate, polyglyceryl-6stearate, polyglyceryl-6 laurate, polyglyceryl-6 myristate,polyglyceryl-6 palmitate, and polyglyceryl-6 linoleate, polyglycerylpolyricinoleates, PEG-20 glyceryl laurate, PEG-30 glyceryl laurate,PEG-40 glyceryl laurate, PEG-20 glyceryl oleate, and PEG-30 glyceryloleate. In another aspect of this embodiment, the tissue includes tissueof one of coronary vasculature, peripheral vasculature, cerebralvasculature, esophagus, airways, sinus, trachea, colon, biliary tract,urinary tract, prostate, and brain passages. In yet another aspect ofthis embodiment, the device includes one of a balloon catheter, aperfusion balloon catheter, a cutting balloon catheter, a scoringballoon catheter, a laser catheter, an atherectomy device, a debulkingcatheter, a stent, a filter, a stent graft, a covered stent, a patch, awire, and a valve.

In yet a further embodiment, the present invention relates to a medicaldevice comprising a layer overlying an exterior surface of the medicaldevice, the layer comprising a therapeutic agent, an additive, and atleast one of an oil, a fatty acid, and a lipid, wherein the additive isone of sorbitan fatty esters, and PEG sorbitan esters. In one aspect ofthis embodiment, the additive is chosen from sorbitan monolaurate,sorbitan monopalmitate, sorbitan monooleate, sorbitan monostearate,Tween 20, Tween 40, Tween 60, Tween 80, PEG-20 sorbitan monolaurate,PEG-20 sorbitan monopalmitate, PEG-20 sorbitan monooleate, and PEG-20sorbitan monostearate. In another aspect of this embodiment, the tissueincludes tissue of one of coronary vasculature, peripheral vasculature,cerebral vasculature, esophagus, airways, sinus, trachea, colon, biliarytract, urinary tract, prostate, and brain passages. In yet anotheraspect of this embodiment, the device includes one of a ballooncatheter, a perfusion balloon catheter, an infusion catheter, perforatedballoon, porous balloon, weeping balloon, a cutting balloon catheter, ascoring balloon catheter, a laser catheter, an atherectomy device, adebulking catheter, a stent, a filter, a stent graft, a covered stent, apatch, a wire, and a valve.

In yet a further embodiment, the present invention relates to a medicaldevice comprising a layer overlying an exterior surface of the medicaldevice, the layer comprising a therapeutic agent, an additive, and atleast one of an oil, a fatty acid, and a lipid, wherein the additive isa chemical compound containing a phenol moiety. In one aspect of thisembodiment, the additive is chosen from p-isononylphenoxypolyglycidol,octoxynol, monoxynol, tyloxapol, octoxynol-9, and monoxynol-9. Inanother aspect of this embodiment, the tissue includes tissue of one ofcoronary vasculature, peripheral vasculature, cerebral vasculature,esophagus, airways, sinus, trachea, colon, biliary tract, urinary tract,prostate, and brain passages. In yet another aspect of this embodiment,the device includes one of a balloon catheter, a perfusion ballooncatheter, an infusion catheter, perforated balloon, porous balloon,weeping balloon, a cutting balloon catheter, a scoring balloon catheter,a laser catheter, an atherectomy device, a debulking catheter, a stent,a filter, a stent graft, a covered stent, a patch, a wire, and a valve.

In yet a further embodiment, the present invention relates to a medicaldevice comprising a layer overlying an exterior surface of the medicaldevice, the layer comprising a therapeutic agent, an additive, and atleast one of an oil, a fatty acid, and a lipid, wherein the additive isa sugar or sugar derivative. In one aspect of this embodiment, theadditive is chosen from sucrose monolaurate, decanoyl-N-methylglucamide,n-decyl-β-D-glucopyranoside, n-decyl-β-D-maltopyranoside,n-dodecyl-β-D-glucopyranoside, n-dodecyl-β-D-maltoside,heptanoyl-N-methylglucamide, n-heptyl-β-D-glucopyranoside,n-heptyl-β-D-thioglucoside, n-hexyl-β-D-glucopyranoside,nonanoyl-N-methylglucamide, n-noyl-β-D-glucopyranoside,octanoyl-N-methylglucamide, n-octyl-β-D-glucopyranoside,octyl-β-D-thioglucopyranoside, D-glucoascorbic acid and its salt,triethanolamine, diethanolamine, meglumine, tromethamine, glucamine,glucosamine, glucoheptonic acid, glucomic acid, hydroxyl ketone,hydroxyl lactone, gluconolactone, glucoheptonolactone, glucooctanoiclactone, gulonic acid lactone, mannoic lactone, ribonic acid lactone,lactobionic acid, glutamic acid, benzyl alcohol, benzoic acid,hydroxybenzoic acid, vanillin, vanillic acid, vanillic aciddiethylamide, lysine acetate salt, gentisic acid, lactobionic acid,lactitol, diethylene glycol, triethylene glycol, tetraethylene glycol,xylitol, 2-ethoxyethanol, sugars, galactose, glucose, mannose, xylose,sucrose, lactose, maltose, sorbitol, cyclodextrin,(2-hydroxypropyl)-cyclodextrin, acetaminophen, ibuprofen, catechin,catechin gallate, methyl paraben, ethyl paraben, propyl paraben, butylparaben, tiletamine, ketamine, propofol, lactic acids, acetic acid,salts of any organic acid and amine described above. In another aspectof this embodiment, the tissue includes tissue of one of coronaryvasculature, peripheral vasculature, cerebral vasculature, esophagus,airways, sinus, trachea, colon, biliary tract, urinary tract, prostate,and brain passages. In yet another aspect of this embodiment, the deviceincludes one of a balloon catheter, a perfusion balloon catheter, acutting balloon catheter, a scoring balloon catheter, a laser catheter,an atherectomy device, a debulking catheter, a stent, a filter, a stentgraft, a covered stent, a patch, a wire, and a valve.

In yet a further embodiment, the present invention relates to a medicaldevice comprising a layer overlying an exterior surface of the medicaldevice, the layer comprising a therapeutic agent, an additive, and atleast one of an oil, a fatty acid, and a lipid, wherein the additive isan ionic surfactant. In one aspect of this embodiment, the additive ischosen from benzalkonium chloride, benzethonium chloride,cetylpyridinium chloride, docecyl trimethyl ammonium bromide, sodiumdocecylsulfates, dialkyl methylbenzyl ammonium chloride, edrophoniumchloride, domiphen bromide, and dialkylesters of sodium sulfonsuccinicacid, sodium dioctyl sulfosuccinate, sodium cholate, and sodiumtaurocholate. In another aspect of this embodiment, the tissue includestissue of one of coronary vasculature, peripheral vasculature, cerebralvasculature, esophagus, airways, sinus, trachea, colon, biliary tract,urinary tract, prostate, and brain passages. In yet another aspect ofthis embodiment, the device includes one of a balloon catheter, aperfusion balloon catheter, an infusion catheter, perforated balloon,porous balloon, weeping balloon, a cutting balloon catheter, a scoringballoon catheter, a laser catheter, an atherectomy device, a debulkingcatheter, a stent, a filter, a stent graft, a covered stent, a patch, awire, and a valve.

In yet a further embodiment, the present invention relates to a medicaldevice comprising a layer overlying an exterior surface of the medicaldevice, the layer comprising a therapeutic agent, an additive, at leastone of an oil, a fatty acid, and a lipid, wherein the additive is avitamin or vitamin derivative. In one aspect of this embodiment, theadditive is chosen from acetiamine, benfotiamine, pantothenic acid,cetotiamine, cycothiamine, dexpanthenol, niacinamide, nicotinic acid andits salts, pyridoxal 5-phosphate, nicotinamide ascorbate, riboflavin,riboflavin phosphate, thiamine, folic acid, menadiol diphosphate,menadione sodium bisulfite, menadoxime, vitamin B12, vitamin K5, vitaminK6, vitamin K6, vitamin U, ergosterol, 1-alpha-hydroxycholecal-ciferol,vitamin D2, vitamin D3, alpha-carotene, beta-carotene, gamma-carotene,vitamin A, fursultiamine, methylolriboflavin, octotiamine,prosultiamine, riboflavine, vintiamol, dihydrovitamin K1, menadioldiacetate, menadiol dibutyrate, menadiol disulfate, menadiol, vitaminK1, vitamin K1 oxide, vitamins K2, and vitamin K—S(II). In anotheraspect of this embodiment, the tissue includes tissue of one of coronaryvasculature, peripheral vasculature, cerebral vasculature, esophagus,airways, sinus, trachea, colon, biliary tract, urinary tract, prostate,and brain passages. In yet another aspect of this embodiment, the deviceincludes one of a balloon catheter, a perfusion balloon catheter, aninfusion catheter, perforated balloon, porous balloon, weeping balloon,a cutting balloon catheter, a scoring balloon catheter, a lasercatheter, an atherectomy device, a debulking catheter, a stent, afilter, a stent graft, a covered stent, a patch, a wire, and a valve.

In yet a further embodiment, the present invention relates to a medicaldevice comprising a layer overlying an exterior surface of the medicaldevice, the layer comprising a therapeutic agent, an additive, and atleast one of an oil, a fatty acid, and a lipid, wherein the additive isan amino acid, an amino acid salt, or an amino acid derivative. In oneaspect of this embodiment, the additive is chosen from alanine,arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine,glycine, histidine, proline, isoleucine, leucine, lysine, methionine,phenylalanine, serine, threonine, tryptophan, tyrosine, valine, andderivatives thereof. In another aspect of this embodiment, the tissueincludes tissue of one of coronary vasculature, peripheral vasculature,cerebral vasculature, esophagus, airways, sinus, trachea, colon, biliarytract, urinary tract, prostate, and brain passages. In yet anotheraspect of this embodiment, the device includes one of a ballooncatheter, a perfusion balloon catheter, an infusion catheter, perforatedballoon, porous balloon, weeping balloon, a cutting balloon catheter, ascoring balloon catheter, a laser catheter, an atherectomy device, adebulking catheter, a stent, a filter, a stent graft, a covered stent, apatch, a wire, and a valve.

In yet a further embodiment, the present invention relates to a medicaldevice for delivering a therapeutic agent to a tissue, the devicecomprising a layer overlying an exterior surface of the medical device,the layer comprising a therapeutic agent, an additive, at least one ofan oil, a fatty acid, and a lipid, wherein the additive is a peptide,oligopeptide, or protein. In one aspect of this embodiment, the additiveis chosen from albumins, immunoglobulins, caseins, hemoglobins,lysozymes, immunoglobins, a-2-macroglobulin, fibronectins, vitronectins,firbinogens, and lipases. In another aspect of this embodiment, thetissue includes tissue of one of coronary vasculature, peripheralvasculature, cerebral vasculature, esophagus, airways, sinus, trachea,colon, biliary tract, urinary tract, prostate, and brain passages. Inyet another aspect of this embodiment, the device includes one of aballoon catheter, a perfusion balloon catheter, an infusion catheter,perforated balloon, porous balloon, weeping balloon, a cutting ballooncatheter, a scoring balloon catheter, a laser catheter, an atherectomydevice, a debulking catheter, a stent, a filter, a stent graft, acovered stent, a patch, a wire, and a valve.

In yet a further embodiment, the present invention relates to a medicaldevice for delivering a therapeutic agent to a tissue, the devicecomprising a layer overlying an exterior surface of the medical device,the layer comprising a therapeutic agent, an additive, and at least oneof an oil, a lipid, and a fatty acid, wherein the additive is an organicacid or an organic acid ester or anhydride. In one aspect of thisembodiment, the additive is chosen from acetic acid and anhydride,benzoic acid and anhydride, diethylenetriaminepentaacetic aciddianhydride, ethylenediaminetetraacetic dianhydride, maleic acid andanhydride, succinic acid and anhydride, diglycolic acid and anhydride,glutaric acid and anhydride, ascorbic acid, citric acid, tartaric acid,lactic acid, oxalic acid aspartic acid, nicotinic acid, and2-pyrrolidone-5-carboxylic acid. In another aspect of this embodiment,the tissue includes tissue of one of coronary vasculature, peripheralvasculature, cerebral vasculature, esophagus, airways, sinus, trachea,colon, biliary tract, urinary tract, prostate, and brain passages. Inyet another aspect of this embodiment, the device includes one of aballoon catheter, a perfusion balloon catheter, a cutting ballooncatheter, a scoring balloon catheter, a laser catheter, an atherectomydevice, a debulking catheter, a stent, a filter, a stent graft, acovered stent, a patch, a wire, and a valve.

Many embodiments of the present invention are particularly useful fortreating vascular disease and for reducing stenosis and late luminalloss, or are useful in the manufacture of devices for that purpose.

It is understood that both the foregoing general description and thefollowing detailed description are exemplary and explanatory only andare not restrictive of the present invention as claimed.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a perspective view of an exemplary embodiment of a ballooncatheter according to the present invention.

FIGS. 2A-2C are cross-sectional views of different embodiments of thedistal portion of the balloon catheter of FIG. 1, taken along line A-A,showing exemplary coating layers.

DETAILED DESCRIPTION OF EXEMPLARY EMBODIMENTS

Embodiments of the present invention relate to medical devices,including particularly balloon catheters and stents, having a rapiddrug-releasing coating and methods for preparing such coated devices.The therapeutic agent according to embodiments of the present inventiondoes not require a delayed or long term release and instead preferablyis released in a very short time period, from seconds to minutes, toprovide a therapeutic effect upon contact with tissue. An object ofembodiments of the present invention is to facilitate rapid andefficient uptake of drug by target tissue during transitory devicedeployment at a target site.

As shown in FIG. 1, in one embodiment, the medical device is a ballooncatheter. The balloon catheter may be any suitable catheter for thedesired use, including conventional balloon catheters known to one ofordinary skill in the art. For example, balloon catheter 10 may includean expandable, inflatable balloon 12 at a distal end of the catheter 10,a handle assembly 16 at a proximal end of the catheter 10, and anelongate flexible member 14 extending between the proximal and distalends. Handle assembly 16 may connect to and/or receive one or moresuitable medical devices, such as a source of inflation media (e.g.,air, saline, or contrast media). Flexible member 14 may be a tube madeof suitable biocompatible material and having one or more lumenstherein. At least one of the lumens is configured to receive inflationmedia and pass such media to balloon 12 for its expansion. The ballooncatheter may be a rapid exchange or over-the-wire catheter and made ofany suitable biocompatible material.

In one embodiment, the present invention provides a medical device fordelivering a therapeutic agent to a tissue. The device includes a layerapplied to an exterior surface of the medical device, such as a ballooncatheter or stent, for example. The layer includes (1) a therapeuticagent, (2) one of an oil, a fatty acid and a lipid, and (3) an additive.For example, as shown in the embodiment depicted in FIG. 2A, the balloon12 is coated with a layer 20 that includes a therapeutic agent, at leastone of an oil, a fatty acid, and a lipid, and an additive. In someembodiments, the layer consists essentially of a therapeutic agent, atleast one of an oil, a fatty acid, and a lipid, and an additive, i.e.,the layer includes only the therapeutic agent, the at least one of anoil, a fatty acid, and a lipid, and the additive, without any othermaterially significant components. In some embodiments, the device mayoptionally include an adherent layer. For example, as shown in theembodiment depicted in FIG. 2B, the balloon 12 is coated with anadherent layer 22. A layer 24 that includes a therapeutic agent, atleast one of an oil, a fatty acid, and a lipid, and an additive isoverlying the adherent layer. The adherent layer, which is a separatelayer underlying the drug coating layer, improves the adherence of thedrug coating layer to the exterior surface of the medical device andprotects coating integrity. For example, if drug, one of an oil, a fattyacid and a lipid, and additive differ in their adherence to the medicaldevice, the adherent layer may prevent differential loss of componentsand maintain drug-to-additive and drug-to-the oil, fatty acid or lipidratio in the coating during transit to a target site for therapeuticintervention. Furthermore, the adherent layer may function to facilitaterapid release of coating layer components off the device surface uponcontact with tissues at the target site. In other embodiments, thedevice may include a top layer. The top layer may reduce loss of thedrug layer before it is brought into contact with target tissues, forexample during transit of the balloon 12 to the site of therapeuticintervention or during the first moments of inflation of balloon 12before coating layer 20 is pressed into direct contact with targettissue.

In embodiments of the coatings for medical devices of the presentinvention, the lipophilic or water-insoluble therapeutic agent isinterdispersed in the matrix or dispersion of the additive, such as anadditive having a hydrophilic part and a drug affinity part, and the atleast one of an oil, a fatty acid and a lipid. The inventor has foundthat, when the coating of a medical device contains a lipophilic orwater-insoluble therapeutic agent and at least one of an oil, a fattyacid and a lipid, but does not contain such an additive, the therapeuticagent cannot elute quickly enough off the surface of the medical devicefor adequate tissue uptake during a brief deployment time of seconds tominutes, because the lipophilic or water-insoluble drug binds the lipid,fatty acid, or oil and the surface of the balloon too tightly. Theinventor has found that, the addition of the additive to the coating,wherein the additive is interspersed or interdispersed with thelipophilic or water-insoluble therapeutic agent and with the at leastone of an oil, a fatty acid, and a lipid, dramatically accelerates theelution of the lipophilic or water-insoluble therapeutic agent and theat least one of an oil, a fatty acid and a lipid off the surface of thedevice and facilitates drug penetration into target tissues. Forexample, an additive may elute rapidly off the surface of the devicewhen the device is deployed in the aqueous environment of the arterialvasculature, and as the additive having a hydrophilic part and a drugaffinity part elutes off the surface of the device, the interdispersedhydrophobic drug and the at least one of an oil, a fatty acid, and alipid are pulled with it. In this example, the additive functions todisrupt the attraction between lipophilic drug and the at least one ofan oil, a fatty acid, and a lipid and the surface of the medical deviceand facilitates dispersal of the therapeutic agent off the device in anaqueous environment. In some cases it may further accelerate passage oflipophilic drug through the water barrier overlying polar head groups ofmembrane bilayers of target tissues to the underlying lipid and cellularproteins with which the lipophilic drug has high affinity.

In one embodiment, the concentration density of the at least onetherapeutic agent applied to the surface of the medical device is fromabout 1 to 20 μg/mm², or more preferably from about 2 to 6 μg/mm². Inone embodiment, the ratio by weight of the therapeutic agent to theadditive in the layer is from about 0.05 to 100, for example, from about0.1 to 5, from 0.5 to 3, and further for example, from about 0.8 to 1.2.In one embodiment, the ratio by weight of the drug to the at least oneof an oil, a fatty acid, and a lipid in the layer is from about 0.05 to100, for example, from about 0.1 to 5, from 0.5 to 2, and further forexample, from about 0.8 to 1.2

In other embodiments, the layer may include a therapeutic agent, atleast one of an oil, a fatty acid, and a lipid, and more than oneadditive. For example, one additive may serve to improve balloonadhesion of another additive or additives, which may be superior atpromoting tissue uptake of drug, or may serve to improve balloonadhesion of the at least one of an oil, a fatty acid, and a lipid.Alternatively, one additive may decrease balloon adhesion of anotheradditive or the at least one of an oil, a fatty acid, and a lipid, inorder to accelerate elution of the therapeutic agent off the surface ofthe device during brief deployment at the target site.

In other embodiments, the layer may include at least one therapeuticagent, at least one of an oil, a fatty acid, and a lipid, at least oneadditive, and at least one polymer carrier for coating of a medicaldevice such as a stent or a balloon. In such embodiments, thetherapeutic agent is not encapsulated in polymer particles.

In another embodiment, the device comprises two layers applied to anexterior surface of the medical device, and particularly a ballooncatheter, for example. The first layer comprises a therapeutic agent.The first layer may optionally comprise at least one of an oil, a fattyacid, and a lipid, and an additive or additives. The second layercomprises at least one of an oil, a fatty acid, and a lipid, and anadditive or additives. The second layer may optionally include at leasta therapeutic agent. When the first and second layers both contain atherapeutic agent, the content of the therapeutic agent in the secondlayer is lower than the content of the therapeutic agent in the firstlayer. In one embodiment, the second layer is overlying the first layer.In this arrangement, the second layer can prevent drug loss duringdeployment of the medical device into body passageways, for example, asa balloon catheter traverses the tortuous anatomy to a tissue site inthe vasculature.

In another embodiment, the device comprises two layers applied to anexterior surface of the medical device, and particularly a ballooncatheter, for example. The first layer comprises a therapeutic agent.The first layer may optionally comprise an additive or additives and mayoptionally comprise at least one of an oil, a fatty acid, and a lipid.The second layer comprises an additive or additives and at least one ofan oil, a fatty acid, and a lipid. The second layer may optionallyinclude at least a therapeutic agent. When the first and second layersboth contain a therapeutic agent, the content of the therapeutic agentin the first layer is lower than the content of the therapeutic agent inthe second layer. In one embodiment, the second layer is overlying thefirst layer. This arrangement is useful, for example, in the case of atherapeutic agent that adheres too tightly to the balloon surface torapidly elute off the balloon when inflated at the target site. In thisarrangement, the first layer functions to facilitate rapid release ofthe bulk of drug, which is in the second layer, off the surface of thedevice while it is inflated at the target site of therapeuticintervention.

In other embodiments, two or more therapeutic agents are used incombination in the drug-additive layer.

In a further embodiment, the device having a two layer coating mayoptionally include an adherent layer. The adherent layer does notcontain a therapeutic agent. For example, as shown in the embodimentdepicted in FIG. 2C, the balloon 12 is coated with an adherent layer 22.A first layer 26 that comprises a therapeutic agent and optionally anadditive or additives and optionally at least one of an oil, a fattyacid, and a lipid, is overlying the adherent layer 22. A second layer 28that comprises an additive, at least one of an oil, a fatty acid, and alipid, and optionally a therapeutic agent is overlying the first layer26. The adherent layer improves the adherence of the first layer to theexterior surface of the medical device and protects the integrity of thefirst layer. For example, if drug and at least one of an oil, a fattyacid, and a lipid and the additive or additives in the first layerdiffer in their strength of adherence to the medical device, theadherent layer may prevent differential loss of components and maintaindrug-to-additive, drug-to at least one of an oil, a fatty acid, and alipid, and additive-to-additive ratio in the first and second layersduring transit to a target site for therapeutic intervention.Furthermore, the adherent layer may function to facilitate rapid elutionof coating layer off the device surface upon contact with tissues at thetarget site. In one embodiment, the first layer, the second layer, andthe adherent layer each contain an additive.

Optionally, post-treatment with dimethylsulfoxide (DMSO) or othersolvent may be advantageous since DMSO may further enhance penetrationand absorption of drug into tissue. DMSO displaces water from the lipidhead groups and protein domains of the membrane lipid bilayer of targetcells to indirectly loosen the lipid structure, accelerating drugabsorption and penetration.

In a further embodiment, the present invention relates to apharmaceutical composition for treating a diseased body lumen orcavities after surgical or interventional procedures (PTCA, PTA, stentplacement, excision of diseased tissue such as cancer, and relieving ortreating stenosis), wherein the pharmaceutical composition comprises atherapeutic agent, at least one of an oil, a fatty acid, and a lipid,and an additive, wherein the additive comprises a hydrophilic part and adrug affinity part, wherein the drug affinity part has an affinity tothe therapeutic agent by hydrogen bonding and/or charge and/or van derWaals interactions, and wherein the therapeutic agent is not enclosed inmicelles or liposomes or encapsulated in polymer particles.

In another embodiment, a method of preventing complications orrecurrence of disease (such as cancer or restenosis) after a surgical orinterventional procedure such as PTCA, PTA, stent deployment, stenosisor plaque removal by debulking, atherectomy, or laser procedures, thepharmaceutical composition is locally delivered at or near the site ofintervention by means of a coated medical device (such as a drug-coatedballoon), or by spray, by injection, or by deposition. For example, thepharmaceutical composition may be delivered by spray, injection, balloonor other method of deposition, into cavities created by surgical removalof cancer tissue in order to reduce the risk of recurrence. As anotherexample, a method for delivering the pharmaceutical compositioncomprises inserting a medical device (such as guide catheter or a druginfusion catheter) into the blood to inject the pharmaceuticalcomposition after a vascular intervention such as PTCA, PTA, or stentplacement to prevent restenosis, wherein the pharmaceutical compositioncomprises a therapeutic agent, at least one of an oil, a fatty acid anda lipid, and an additive, wherein the additive comprises a hydrophilicpart and a drug affinity part, wherein the drug affinity part has anaffinity to the therapeutic agent by hydrogen bonding and/or chargeand/or Van der Waals interactions, and wherein the therapeutic agent isnot enclosed in micelles or liposomes or encapsulated in polymerparticles.

Many embodiments of the present invention are particularly useful fortreating vascular disease and for reducing stenosis and late luminalloss, or are useful in the manufacture of devices for that purpose.

Oil, Fatty Acid and Lipid

The oil, fatty acid, and lipid of embodiments of the present inventionare hydrophobic. They are not soluble in water. The lipophilic orwater-insoluble therapeutic agents, such as paclitaxel, rapamycin andtheir analogues, are soluble in the oil, fatty acid, and lipid. Drugrelease from coatings of water-insoluble drugs and at least one of anoil, a fatty acid, and a lipid that lack the additive, such as ahydrophilic additive, is very slow, in the range of days to months.

The oil, fatty acid, and lipid in embodiments of the inventions hereininclude, for example, soybean oil, vegetable oil, flower oil, animaloil, marine oil, butterfat, coconut oil, palm oil, olive oil, peanutoil, fish oil, butanoic acid, hexanoic acid, octanoic acid, decanoicacid, dodecanoic acid, tetradecanoic acid, hexadecanoic acid,octadecanoic acid, octadecatrienoic acid, eicosanoic acid, eicosenoicacid, eicosatetraenoic acid, eicosapentaenoic acid, docosahexaenoicacid, tocotrienol, butyric acid, caproic acid, caprylic acid, capricacid, lauric acid, myristic acid, palmitic acid, palmitoleic acid,stearic acid, oleic acid, vaccenic acid, linoleic acid, alpha-linolenicacid, gamma-linolenic acid, behenic acid, erucic acid, lignoceric acid,natural or synthetic phospholipids, mono-, di-, or triacylglycerols,cardiolipin, phosphatidylglycerol, phosphatidic acid,phosphatidylcholine, alpha tocoferol, phosphatidylethanolamine,sphingomyelin, phosphatidylserine, phosphatidylinositol,dimyristoylphosphatidylcholine, dioleoylphosphatidylcholine,dipalmitoylphosphatidylcholine, distearoylphosphatidylcholine,phosphatidylethanolamines phosphatidylglycerols, sphingolipids,prostaglandins, gangliosides, neobee, niosomes and derivatives. Thereare many other oils, fatty acids, and lipids known in the art that areuseful in embodiments of the present invention.

Additive

In embodiments of the present invention, the additive is hydrophilic. Itis water-soluble. In embodiments of the present invention, the additiveis interdispersed with the lipophilic or water-insoluble drug and atleast one of an oil, a fatty acid, and a lipid in the coating of amedical device. In some embodiments, the additive accelerates theelution of the lipophilic or water-insoluble therapeutic agent and theat least one of an oil, a fatty acid, and a lipid off the surface of thedevice and facilitates drug penetration into target tissues. In someembodiments, the additive may disrupt the hydrophobic attractionsbetween lipophilic drug and the at least one of an oil, a fatty acid,and a lipid and the surface of the medical device. In addition, in someembodiments, as the additive elutes off the surface of the device it mayalso disperse the therapeutic agent and the at least one of an oil, afatty acid, and a lipid off the surface of the device and facilitatetissue penetration of the therapeutic agent.

In embodiments of the present invention, the additive has two parts: ahydrophilic part and a drug affinity part. The drug affinity part is ahydrophobic part or has an affinity to the therapeutic agent by hydrogenbonding and/or charge and/or van der Waals interactions. The drugaffinity part of the additive may bind the lipophilic drug, such asrapamycin or paclitaxel. Binding or affinity between the drug affinitypart of the additive and the drug may be relatively weak. For example,the drug affinity part might comprise hydroxyl groups, which are able toform hydrogen bonds with hydroxyl groups of the drug.

In some embodiments, the additive accelerates diffusion and increasespermeation of the drug into tissue. It may facilitate rapid movement ofdrug off the medical device during deployment at the target site bypreventing hydrophobic drug molecules from clumping to each other and tothe at least one of an oil, a fatty acid, and a lipid, and to thesurface of the device, increasing drug solubility in interstitialspaces, and/or accelerating drug passage through polar head groups tothe lipid bilayer of cell membranes of target tissues. In oneembodiment, the additives of the present invention have two parts thatfunction together to facilitate rapid release of drug off the devicesurface and uptake by target tissue during deployment (by acceleratingdrug contact with tissues for which drug has high affinity) whilepreventing the premature release of drug from the device surface priorto device deployment at the target site.

In embodiments of the present invention, the therapeutic agent israpidly released after the medical device is brought into contact withtissue and is readily absorbed. For example, certain embodiments ofdevices of the present invention include drug coated balloon cathetersthat deliver a lipophilic anti-proliferative pharmaceutical (such aspaclitaxel or rapamycin) to vascular tissue through brief, directpressure contact at high drug concentration during balloon angioplasty.The lipophilic drug is preferentially retained in target tissue at thedelivery site, where it inhibits hyperplasia and restenosis yet allowsendothelialization. In these embodiments, coating formulations of thepresent invention not only facilitate rapid release of drug from theballoon surface and transfer of drug into target tissues duringdeployment, but also prevent drug from diffusing away from the deviceduring transit through tortuous arterial anatomy prior to reaching thetarget site and from exploding off the device during the initial phaseof balloon inflation, before the drug coating is pressed into directcontact with the surface of the vessel wall.

In embodiments of the present invention, the additive has functionalgroups that can form hydrogen bonds with drug and with itself. Thesefunctional groups include hydroxyl groups, amine groups, amide groups,carbonyl groups, carboxylic acid and anhydrides, ethyl oxide, ethylglycol, polyethylene glycol, ascorbic acid, amino acid, amino alcohol,glucose, sucrose, sorbitan, glycerol, polyalcohol, phosphates, sulfates,organic salts and their substituted molecules, among others. One or morehydroxyl, carboxyl, acid, amide or amine groups, for example, may beadvantageous since they easily displace water molecules that arehydrogen-bound to polar head groups and surface proteins of cellmembranes and may function to remove this barrier between hydrophobicdrug and cell membrane lipid. These parts can dissolve in water andpolar solvents. The therapeutic agent is not enclosed in micelles orliposomes or encapsulated in polymer particles. The additive ofembodiments of the present invention facilitates rapid movement of drugoff the medical device during deployment and into target tissues.

The additives in embodiments of the present invention are surfactantsand chemical compounds with one or more hydroxyl, amino, carbonyl,carboxyl, acid, amide or ester moieties. The surfactants include ionic,nonionic, aliphatic, and aromatic surfactants. The chemical compoundswith one or more hydroxyl, amino, carbonyl, carboxyl, acid, amide orester moieties are chosen from amino alcohols, hydroxyl carboxylic acidand anhydrides, ethyl oxide, ethyl glycols, amino acids, peptides,proteins, sugars, glucose, sucrose, sorbitan, glycerol, polyalcohol,phosphates, sulfates, organic acids, esters, salts, vitamins, and theirsubstituted molecules.

The inventor has performed experiments with some of these surfactantsand chemical compounds, combined alone with a lipophilic orwater-insoluble therapeutic agent to form the coating of a medicaldevice. In at least certain experiments, a relatively large amount ofthe therapeutic agent is lost from the coating of the device during itstransit to the target site, for example through the arterial vasculatureto a stenotic vessel, and with less of the therapeutic agent remainingto provide a therapeutic effect when the coated device finally reachesthe target site of therapeutic intervention. The further inclusion of atleast one of an oil, a fatty acid, and a lipid in the coating results inless loss of therapeutic agent during transit. In such situations, theaddition of the at least one of an oil, fatty acid, and lipid, whichtightly binds the lipophilic drug, prevents premature loss oftherapeutic agent from the device, but still allows rapid elution whenthe device is deployed for a brief period of time. Relatively more oil,fatty acid, or lipid may be needed in coatings that include an additivethat poorly retains the therapeutic agent on the medical device duringtransit. Alternatively, in coatings for medical devices that do notinclude an oil, a fatty acid or a lipid, retention of therapeutic agentduring transit may be improved by instead including an additionaladditive that is relatively hydrophobic.

The inventor has determined experimentally that some of thesesurfactants when combined alone with a lipophilic or water-insolubletherapeutic agent to form the coating of a medical device, thetherapeutic agent release from the balloon catheters was acceleratedwhen the ratio of paclitaxel to the surfactant was in a range of from0.1 to 0.8. In such situations, a lower amount of surfactant relative topaclitaxel accelerated the drug releasing, and a higher amount of thesurfactant reduced the drug releasing. When some of these surfactantsare combined alone with a lipophilic or water-insoluble therapeuticagent to form the coating of a medical device, a relatively large amountof the therapeutic agent is lost from the coating of the device duringits transit to the target site, for example through the arterialvasculature to a stenotic vessel, with less of the therapeutic agentremaining to provide a therapeutic effect when the coated device finallyreaches the target site of therapeutic intervention. The furtherinclusion of the at least one of an oil, fatty acid, and lipid in thecoating with a relatively small amount of the surfactant to slow drugreleasing results in less loss of therapeutic agent during transit. Insuch situations, the addition of the at least one of an oil, a fattyacid, and a lipid, which tightly binds the lipophilic drug, reducespremature loss of therapeutic agent from the device, but still allowsrapid elution when the device is deployed for a brief period of time.

As is well known in the art, the terms “hydrophilic” and “hydrophobic”are relative terms. To function as an additive in exemplary embodimentsof the present invention, the compound includes polar or chargedhydrophilic moieties. In certain embodiments, the hydrophilic additivehas a drug affinity part that includes a nonpolar, hydrophobic orlipophilic moiety.

An empirical parameter commonly used in medicinal chemistry tocharacterize the relative hydrophilicity and hydrophobicity ofpharmaceutical compounds is the partition coefficient, P, the ratio ofconcentrations of unionized compound in the two phases of a mixture oftwo immiscible solvents, usually octanol and water, such thatP=([solute]octanol/[solute]water). Compounds with higher log Ps are morehydrophobic, while compounds with lower log Ps are more hydrophilic.Lipinski's rule suggests that pharmaceutical compounds having log P<5are typically more membrane permeable. For purposes of certainembodiments of the present invention, it is preferable that the additivehas log P less than log P of the drug to be formulated (as an example,log P of paclitaxel is 7.4). Furthermore, it is preferable that theadditive has log P less than the at least one of an oil, a fatty acid,and a lipid. A greater log P difference between the drug and theadditive can facilitate phase separation of drug. For example, if log Pof the additive is much lower than log P of the drug, the additive mayaccelerate the release of drug in an aqueous environment from the atleast one of an oil, a fatty acid, and a lipid and from the surface of adevice to which drug might otherwise tightly adhere, therebyaccelerating drug delivery to tissue during brief deployment at the siteof intervention. In certain embodiments of the present invention, log Pof the additive is negative. In other embodiments, log P of the additiveis less than log P of the drug and less than log P of the at least oneof an oil, a fatty acid, and a lipid. While a compound's octanol-waterpartition coefficient P or log P is useful as a measurement of relativehydrophilicity and hydrophobicity, it is merely a rough guide that maybe useful in defining suitable additives for use in embodiments of thepresent invention.

Suitable additives that can be used in embodiments of the presentinvention include, without limitation, organic and inorganicpharmaceutical excipients, natural products and derivatives thereof(such as sugars, vitamins, amino acids, peptides, proteins, and fattyacids), low molecular weight oligomers, surfactants (anionic, cationic,non-ionic, and ionic), and mixtures thereof. The following detailed listof additives useful in the present invention is provided for exemplarypurposes only and is not intended to be comprehensive. Many otheradditives may be useful for purposes of the present invention.

Surfactants

The surfactant can be any surfactant suitable for use in pharmaceuticalcompositions. Such surfactants can be anionic, cationic, zwitterionic ornon-ionic. Mixtures of surfactants are also within the scope of theinvention, as are combinations of surfactant and other additives.Surfactants often have one or more long aliphatic chains such as fattyacids that may insert directly into lipid bilayers of cell membranes toform part of the lipid structure, while other components of thesurfactants loosen the lipid structure and enhance drug penetration andabsorption. The contrast agent iopromide does not have these properties.

An empirical parameter commonly used to characterize the relativehydrophilicity and hydrophobicity of surfactants is thehydrophilic-lipophilic balance (“HLB” value). Surfactants with lower HLBvalues are more hydrophobic, and have greater solubility in oils, whilesurfactants with higher HLB values are more hydrophilic, and havegreater solubility in aqueous solutions. Using HLB values as a roughguide, hydrophilic surfactants are generally considered to be thosecompounds having an HLB value greater than about 10, as well as anionic,cationic, or zwitterionic compounds for which the HLB scale is notgenerally applicable. Similarly, hydrophobic surfactants are compoundshaving an HLB value less than about 10. In certain embodiments of thepresent invention, a higher HLB value is preferred, since increasedhydrophilicity may facilitate release of hydrophobic drug from thesurface of the device. In one embodiment, the HLB of the surfactantadditive is higher than 10. In another embodiment, the additive HLB ishigher than 14. Alternatively, surfactants having lower HLB may bepreferred when used to prevent drug loss prior to device deployment atthe target site, for example in a top coat over a drug layer that has avery hydrophilic additive.

It should be understood that the HLB value of a surfactant is merely arough guide generally used to enable formulation of industrial,pharmaceutical and cosmetic emulsions, for example. For many importantsurfactants, including several polyethoxylated surfactants, it has beenreported that HLB values can differ by as much as about 8 HLB units,depending upon the empirical method chosen to determine the HLB value(Schott, J. Pharm. Sciences, 79(1), 87-88 (1990)). Keeping theseinherent difficulties in mind, and using HLB values as a guide,surfactants may be identified that have suitable hydrophilicity orhydrophobicity for use in embodiments of the present invention, asdescribed herein.

PEG-Fatty Acids and PEG-Fatty Acid Mono and Diesters

Although polyethylene glycol (PEG) itself does not function as asurfactant, a variety of PEG-fatty acid esters have useful surfactantproperties. Among the PEG-fatty acid monoesters, esters of lauric acid,oleic acid, and stearic acid are most useful in embodiments of thepresent invention. Preferred hydrophilic surfactants include PEG-8laurate, PEG-8 oleate, PEG-8 stearate, PEG-9 oleate, PEG-10 laurate,PEG-10 oleate, PEG-12 laurate, PEG-12 oleate, PEG-15 oleate, PEG-20laurate and PEG-20 oleate. The HLB values are in the range of 4-20.

Polyethylene glycol fatty acid diesters are also suitable for use assurfactants in the compositions of embodiments of the present invention.Most preferred hydrophilic surfactants include PEG-20 dilaurate, PEG-20dioleate, PEG-20 distearate, PEG-32 dilaurate and PEG-32 dioleate. TheHLB values are in the range of 5-15.

In general, mixtures of surfactants are also useful in embodiments ofthe present invention, including mixtures of two or more commercialsurfactants as well as mixtures of surfactants with another additive oradditives. Several PEG-fatty acid esters are marketed commercially asmixtures or mono- and diesters.

Polyethylene Glycol Glycerol Fatty Acid Esters

Preferred hydrophilic surfactants are PEG-20 glyceryl laurate, PEG-30glyceryl laurate, PEG-40 glyceryl laurate, PEG-20 glyceryl oleate, andPEG-30 glyceryl oleate.

Alcohol-Oil Transesterification Products

A large number of surfactants of different degrees of hydrophobicity orhydrophilicity can be prepared by reaction of alcohols or polyalcoholwith a variety of natural and/or hydrogenated oils. Most commonly, theoils used are castor oil or hydrogenated castor oil, or an ediblevegetable oil such as corn oil, olive oil, peanut oil, palm kernel oil,apricot kernel oil, or almond oil. Preferred alcohols include glycerol,propylene glycol, ethylene glycol, polyethylene glycol, sorbitol, andpentaerythritol. Among these alcohol-oil transesterified surfactants,preferred hydrophilic surfactants are PEG-35 castor oil (Incrocas-35),PEG-40 hydrogenated castor oil (Cremophor RH 40), PEG-25 trioleate(TAGAT® TO), PEG-60 corn glycerides (Crovol M70), PEG-60 almond oil(Crovol A70), PEG-40 palm kernel oil (Crovol PK70), PEG-50 castor oil(Emalex C-50), PEG-50 hydrogenated castor oil (Emalex HC-50), PEG-8caprylic/capric glycerides (Labrasol), and PEG-6 caprylic/capricglycerides (Softigen 767). Preferred hydrophobic surfactants in thisclass include PEG-5 hydrogenated castor oil, PEG-7 hydrogenated castoroil, PEG-9 hydrogenated castor oil, PEG-6 corn oil (Labrafil® M 2125CS), PEG-6 almond oil (Labrafil® M 1966 CS), PEG-6 apricot kernel oil(Labrafil® M 1944 CS), PEG-6 olive oil (Labrafil® M 1980 CS), PEG-6peanut oil (Labrafil® M 1969 CS), PEG-6 hydrogenated palm kernel oil(Labrafil® M 2130 BS), PEG-6 palm kernel oil (Labrafil® M 2130 CS),PEG-6 triolein (Labrafil®b M 2735 CS), PEG-8 corn oil (Labrafil® WL 2609BS), PEG-20 corn glycerides (Crovol M40), and PEG-20 almond glycerides(Crovol A40).

Polyglyceryl Fatty Acids

Polyglycerol esters of fatty acids are also suitable surfactants for usein embodiments of the present invention. Among the polyglyceryl fattyacid esters, preferred hydrophobic surfactants include polyglyceryloleate (Plurol Oleique), polyglyceryl-2 dioleate (Nikkol DGDO),polyglyceryl-10 trioleate, polyglyceryl stearate, polyglyceryl laurate,polyglyceryl myristate, polyglyceryl palmitate, and polyglyceryllinoleate. Preferred hydrophilic surfactants include polyglyceryl-10laurate (Nikkol Decaglyn 1-L), polyglyceryl-10 oleate (Nikkol Decaglyn1-0), and polyglyceryl-10 mono, dioleate (Caprol® PEG 860),polyglyceryl-10 stearate, polyglyceryl-10 laurate, polyglyceryl-10myristate, polyglyceryl-10 palmitate, polyglyceryl-10 linoleate,polyglyceryl-6 stearate, polyglyceryl-6 laurate, polyglyceryl-6myristate, polyglyceryl-6 palmitate, and polyglyceryl-6 linoleate.Polyglyceryl polyricinoleates (Polymuls) are also preferred surfactants.

Propylene Glycol Fatty Acid Esters

Esters of propylene glycol and fatty acids are suitable surfactants foruse in embodiments of the present invention. In this surfactant class,preferred hydrophobic surfactants include propylene glycol monolaurate(Lauroglycol FCC), propylene glycol ricinoleate (Propymuls), propyleneglycol monooleate (Myverol P-O6), propylene glycol dicaprylate/dicaprate(Captex® 200), and propylene glycol dioctanoate (Captex® 800).

Sterol and Sterol Derivatives

Sterols and derivatives of sterols are suitable surfactants for use inembodiments of the present invention. Preferred derivatives include thepolyethylene glycol derivatives. A preferred surfactant in this class isPEG-24 cholesterol ether (Solulan C-24).

Polyethylene Glycol Sorbitan Fatty Acid Esters

A variety of PEG-sorbitan fatty acid esters are available and aresuitable for use as surfactants in embodiments of the present invention.Among the PEG-sorbitan fatty acid esters, preferred surfactants includePEG-20 sorbitan monolaurate (Tween-20), PEG-20 sorbitan monopalmitate(Tween-40), PEG-20 sorbitan monostearate (Tween-60), and PEG-20 sorbitanmonooleate (Tween-80).

Polyethylene Glycol Alkyl Ethers

Ethers of polyethylene glycol and alkyl alcohols are suitablesurfactants for use in embodiments of the present invention. Preferredethers include PEG-3 oleyl ether (Volpo 3) and PEG-4 lauryl ether (Brij30).

Sugar and its Derivatives

Sugar derivatives are suitable surfactants for use in embodiments of thepresent invention. Preferred surfactants in this class include sucrosemonopalmitate, sucrose monolaurate, decanoyl-N-methylglucamide,n-decyl-β-D-glucopyranoside, n-decyl-β-D-maltopyranoside,n-dodecyl-β-D-glucopyranoside, n-dodecyl-β-D-maltoside,heptanoyl-N-methylglucamide, n-heptyl-β-D-glucopyranoside,n-heptyl-β-D-thioglucoside, n-hexyl-β-D-glucopyranoside,nonanoyl-N-methylglucamide, n-noyl-β-D-glucopyranoside,octanoyl-N-methylglucamide, n-octyl-β-D-glucopyranoside, andoctyl-β-D-thioglucopyranoside.

Polyethylene Glycol Alkyl Phenols

Several PEG-alkyl phenol surfactants are available, such as PEG-10-100nonyl phenol and PEG-15-100 octyl phenol ether, Tyloxapol, octoxynol,nonoxynol, and are suitable for use in embodiments of the presentinvention.

Polyoxyethylene-Polyoxypropylene (POE-POP) Block Copolymers

The POE-POP block copolymers are a unique class of polymericsurfactants. The unique structure of the surfactants, with hydrophilicPOE and hydrophobic POP moieties in well-defined ratios and positions,provides a wide variety of surfactants suitable for use in embodimentsof the present invention. These surfactants are available under varioustrade names, including Synperonic PE series (ICI); Pluronic® series(BASF), Emkalyx, Lutrol (BASF), Supronic, Monolan, Pluracare, andPlurodac. The generic term for these polymers is “poloxamer” (CAS9003-11-6). These polymers have the formula:

HO (C₂H₄O)_(a)(C₃H₆O)_(b)(C₂H₄O)_(a)H where “a” and “b” denote thenumber of polyoxyethylene and polyoxypropylene units, respectively.

Preferred hydrophilic surfactants of this class include Poloxamers 108,188, 217, 238, 288, 338, and 407. Preferred hydrophobic surfactants inthis class include Poloxamers 124, 182, 183, 212, 331, and 335.

Sorbitan Fatty Acid Esters

Sorbitan esters of fatty acids are suitable surfactants for use inembodiments of the present invention. Among these esters, preferredhydrophobic surfactants include sorbitan monolaurate (Arlacel 20),sorbitan monopalmitate (Span-40), and sorbitan monooleate (Span-80),sorbitan monostearate.

The sorbitan monopalmitate, an amphiphilic derivative of Vitamin C(which has Vitamin C activity), can serve two important functions insolubilization systems. First, it possesses effective polar groups thatcan modulate the microenvironment. These polar groups are the samegroups that make vitamin C itself (ascorbic acid) one of the mostwater-soluble organic solid compounds available: ascorbic acid issoluble to about 30 wt/wt % in water (very close to the solubility ofsodium chloride, for example). And second, when the pH increases so asto convert a fraction of the ascorbyl palmitate to a more soluble salt,such as sodium ascorbyl palmitate.

Ionic Surfactants

Ionic surfactants, including cationic, anionic and zwitterionicsurfactants, are suitable hydrophilic surfactants for use in embodimentsof the present invention. Preferred ionic surfactants include quaternaryammonium salts, fatty acid salts and bile salts. Specifically, preferredionic surfactants include benzalkonium chloride, benzethonium chloride,cetylpyridinium chloride, docecyl trimethyl ammonium bromide, sodiumdocecylsulfates, dialkyl methylbenzyl ammonium chloride, edrophoniumchloride, domiphen bromide, dialkylesters of sodium sulfonsuccinic acid,sodium dioctyl sulfosuccinate, sodium cholate, and sodium taurocholate.These quaternary ammonium salts are preferred additives. They can bedissolved in both organic solvents (such as ethanol, acetone, andtoluene) and water. This is especially useful for medical devicecoatings because it simplifies the preparation and coating process andhas good adhesive properties. Water insoluble drugs are commonlydissolved in organic solvents.

Chemical Compounds with One or More Hydroxyl, Amino, Carbonyl, Carboxyl,Acid, Amide or Ester Moieties

The chemical compounds with one or more hydroxyl, amino, carbonyl,carboxyl, acid, amide or ester moieties include amino alcohols, hydroxylcarboxylic acid, ester, and anhydrides, hydroxyl ketone, hydroxyllactone, hydroxyl ester, sugar phosphate, sugar sulfate, ethyl oxide,ethyl glycols, amino acids, peptides, proteins, sorbitan, glycerol,polyalcohol, phosphates, sulfates, organic acids, esters, salts,vitamins, combinations of amino alcohols and organic acids, and theirsubstituted molecules. Hydrophilic chemical compounds with one or morehydroxyl, amino, carbonyl, carboxyl, acid, amide or ester moietieshaving molecular weight less than 5,000-10,000 are preferred in certainembodiments. In other embodiments, molecular weight of the additive withone or more hydroxyl, amino, carbonyl, carboxyl, acid, amide, or estermoieties is preferably less than 1000-5,000, or more preferably lessthan 750-1,000, or most preferably less than 750. In these embodiments,the molecular weight of the additive is preferred to be less than thatof the drug to be delivered. The molecular weight of the additive ispreferred to be higher than 80 since molecules with molecular weightless than 80 very easily evaporate and do not stay in the coating of amedical device. Small molecules can diffuse quickly. They can releasethemselves easily from the delivery balloon, accelerating release ofdrug, and they can diffuse away from drug when the drug binds tissue ofthe body lumen.

Fat-Soluble Vitamins and Salts Thereof

Vitamins A, D, E and K in many of their various forms and provitaminforms are considered as fat-soluble vitamins and in addition to these anumber of other vitamins and vitamin sources or close relatives are alsofat-soluble and have polar groups, and relatively high octanol-waterpartition coefficients. Clearly, the general class of such compounds hasa history of safe use and high benefit to risk ratio, making them usefulas additives in embodiments of the present invention. Derivatives offat-soluble vitamins useful in embodiments of the present invention mayeasily be obtained via well known chemical reactions with hydrophilicmolecules.

The following are examples of fat-soluble vitamin derivatives and/orsources: Alpha-tocopherol, beta-tocopherol, gamma-tocopherol,delta-tocopherol, tocopherol acetate, ergosterol,1-alpha-hydroxycholecal-ciferol, vitamin D2, vitamin D3, alpha-carotene,beta-carotene, gamma-carotene, vitamin A, fursultiamine,methylolriboflavin, octotiamine, prosultiamine, riboflavine, vintiamol,dihydrovitamin K1, menadiol diacetate, menadiol dibutyrate, menadioldisulfate, menadiol, vitamin K1, vitamin K1 oxide, vitamins K2, andvitamin K—S(II). Folic acid is also of this type; it can be formulatedin the free acid form, but it is water-soluble at physiological pH.Other derivatives of fat-soluble vitamins useful in embodiments of thepresent invention may easily be obtained via well known chemicalreactions with hydrophilic molecules.

Water-Soluble Vitamins and their Amphiphilic Derivatives

Vitamins B, C, U, pantothenic acid, folic acid, and some of themenadione-related vitamins/provitamins in many of their various formsare considered water-soluble vitamins. These may also be conjugated orcomplexed with hydrophobic moieties or multivalent ions into amphiphilicforms having relatively high octanol-water partition coefficients andpolar groups. Again, such compounds can be of low toxicity and highbenefit to risk ratio, making them useful as additives in embodiments ofthe present invention. Salts of these can also be useful as additives inthe present invention. Examples of water-soluble vitamins andderivatives include, without limitation, acetiamine, benfotiamine,pantothenic acid, cetotiamine, cycothiamine, dexpanthenol, niacinamide,nicotinic acid, pyridoxal 5-phosphate, nicotinamide ascorbate,riboflavin, riboflavin phosphate, thiamine, folic acid, menadioldiphosphate, menadione sodium bisulfite, menadoxime, vitamin B12,vitamin K5, vitamin K6, vitamin K6, and vitamin U. Also, as mentionedabove, folic acid is, over a wide pH range including physiological pH,water-soluble, as a salt.

Compounds in which an amino or other basic group is present can easilybe modified by simple acid-base reaction with a hydrophobicgroup-containing acid such as a fatty acid (especially lauric, oleic,myristic, palmitic, stearic, or 2-ethylhexanoic acid), low-solubilityamino acid, benzoic acid, salicylic acid, or an acidic fat-solublevitamin (such as riboflavin). Other compounds might be obtained byreacting such an acid with another group on the vitamin such as ahydroxyl group to form a linkage such as an ester linkage, etc.Derivatives of a water-soluble vitamin containing an acidic group can begenerated in reactions with a hydrophobic group-containing reactant suchas stearylamine or riboflavine, for example, to create a compound thatis useful in embodiments of the present invention. The linkage of apalmitate chain to vitamin C yields ascorbyl palmitate.

Amino Acids and their Salts

Alanine, arginine, asparagines, aspartic acid, cysteine, cystine,glutamic acid, glutamine, glycine, histidine, proline, isoleucine,leucine, lysine, methionine, phenylalanine, serine, threonine,tryptophan, tyrosine, valine, and derivatives thereof are other usefuladditives in embodiments of the invention.

Certain amino acids, in their zwitterionic form and/or in a salt formwith a monovalent or multivalent ion, have polar groups, relatively highoctanol-water partition coefficients, and are useful in embodiments ofthe present invention. In the context of the present disclosure we take“low-solubility amino acid” to mean an amino acid which has a solubilityin unbuffered water of less than about 4% (40 mg/ml). These includeCystine, tyrosine, tryptophan, leucine, isoleucine, phenylalanine,asparagine, aspartic acid, glutamic acid, and methionine.

Amino acid dimers, sugar-conjugates, and other derivatives are alsouseful. Through simple reactions well known in the art hydrophilicmolecules may be joined to hydrophobic amino acids, or hydrophobicmolecules to hydrophilic amino acids, to make additional additivesuseful in embodiments of the present invention.

Catecholamines, such as dopamine, levodopa, carbidopa, and DOPA, arealso useful as additives.

Oligopeptides, Peptides and Proteins

Oligopeptides and peptides are useful as additives, since hydrophobicand hydrophilic amino acids may be easily coupled and various sequencesof amino acids may be tested to maximally facilitate permeation oftissue by drug.

Proteins are also useful as additives in embodiments of the presentinvention. Serum albumin, for example, is a preferred additive since itis water-soluble and contains significant hydrophobic parts to binddrug: paclitaxel is 89% to 98% protein-bound after human intravenousinfusion, and rapamycin is 92% protein bound, primarily (97%) toalbumin. Furthermore, paclitaxel solubility in PBS increases over20-fold with the addition of BSA. Albumin is naturally present at highconcentrations in serum and is thus very safe for human intravascularuse.

Other useful proteins include, without limitation, other albumins,immunoglobulins, caseins, hemoglobins, lysozymes, immunoglobins,a-2-macroglobulin, fibronectins, vitronectins, firbinogens, lipases, andthe like.

Organic Acids and their Esters and Anhydrides

Examples are acetic acid and anhydride, benzoic acid and anhydride,diethylenetriaminepentaacetic acid dianhydride,ethylenediaminetetraacetic dianhydride, maleic acid and anhydride,succinic acid and anhydride, diglycolic anhydride, glutaric anhydride,ascorbic acid, citric acid, tartaric acid, lactic acid, oxalic acidaspartic acid, nicotinic acid, 2-pyrrolidone-5-carboxylic acid, and2-pyrrolidone.

These esters and anhydrides are soluble in organic solvents such asethanol, acetone, methylethylketone, ethylacetate. The water insolubledrugs can be dissolved in organic solvent with these esters andanhydrides, then coated easily on to the medical device, then hydrolyzedunder high pH conditions. The hydrolyzed anhydrides or esters are acidsor alcohols, which are water-soluble and can effectively carry the drugsoff the device into the vessel walls.

Other chemical compounds with one or more hydroxyl, amine, carbonyl,carboxyl, or ester moieties

The additives include amino alcohols, alcohols, amines, acids, amidesand hydroxyl acids in both cyclo and linear aliphatic and aromaticgroups. Examples are L-ascorbic acid and its salt, D-glucoascorbic acidand its salt, tromethamine, triethanolamine, diethanolamine, meglumine,glucamine, amine alcohols, glucoheptonic acid, glucomic acid, hydroxylketone, hydroxyl lactone, gluconolactone, glucoheptonolactone,glucooctanoic lactone, gulonic acid lactone, mannoic lactone, ribonicacid lactone, lactobionic acid, glucosamine, glutamic acid, benzylalcohol, benzoic acid, hydroxybenzoic acid, propyl 4-hydroxybenzoate,lysine acetate salt, gentisic acid, lactobionic acid, lactitol,sorbitol, glucose, ribose, arabinose, lyxose, xylose, fructose, mannose,glucitol, sugars, sugar phosphates, glucopyranose phosphate, sugarsulphates, sinapic acid, vanillic acid, vanillin, methyl paraben, propylparaben, diethylene glycol, triethylene glycol, tetraethylene glycol,xylitol, 2-ethoxyethanol, sugars, galactose, glucose, mannose, xylose,sucrose, lactose, maltose, sorbitol, cyclodextrin,(2-hydroxypropyl)-cyclodextrin, acetaminophen, ibuprofen, retinoic acid,lysine acetate, gentisic acid, catechin, catechin gallate, tiletamine,ketamine, propofol, lactic acids, acetic acid, salts of any organic acidand amine described above, polyglycidol, glycerols, and derivativesthereof.

Combinations of additives are also useful for purposes of the presentinvention.

One embodiment comprises the combination or mixture of two hydrophilicadditives, for example, a first additive comprising a surfactant and asecond additive comprising a chemical compound with one or morehydroxyl, amine, carbonyl, carboxyl, or ester moieties.

The combination or mixture of a surfactant and a small water-solublemolecule (the chemical compounds with one or more hydroxyl, amine,carbonyl, carboxyl, or ester moieties) has advantages. Formulationscomprising mixtures of the two additives with water-insoluble drug arein certain cases superior to either alone. The hydrophobic drugs bindextremely water-soluble small molecules more poorly than they dosurfactants. They are often phase separated from the small water-solublemolecules, which can lead to suboptimal coating uniformity andintegrity. The water-insoluble drug has Log P higher than both that ofthe surfactant and that of small water-soluble molecules. However, Log Pof the surfactant is typically higher than Log P of the chemicalcompounds with one or more hydroxyl, amine, carbonyl, carboxyl, or estermoieties. The surfactant has a relatively high Log P (usually above 0)and the water-soluble molecules have low Log P (usually below 0). Somesurfactants, when used as additives in embodiments of the presentinvention, adhere so strongly to the water-insoluble drug and the atleast one of an oil, a fatty acid, and a lipid and the surface of themedical device that drug is not able to rapidly release from the surfaceof the medical device at the target site. On the other hand, some of thewater-soluble small molecules (with one or more hydroxyl, amine,carbonyl, carboxyl, or ester moieties) adhere so poorly to the medicaldevice that they release drug before it reaches the target site, forexample, into serum during the transit of a coated balloon catheter tothe site targeted for intervention. Surprisingly, by adjusting the ratioof the concentrations of the small hydrophilic molecules, thesurfactants, and the at least one of an oil, a fatty acid, and a lipidin the coating, the inventor has found that the coating stability duringtransit and rapid drug release when inflated and pressed against tissuesof the lumen wall at the target site of therapeutic intervention issuperior to a coating comprising any of these components alone.Furthermore, the miscibility and compatibility of the water-insolubledrug and the highly water-soluble molecules is improved by the presenceof the surfactant and the at least one of an oil, a fatty acid, and alipid. The surfactant also improves coating uniformity and integrity byits good adhesion to the drug and to the small molecules. The long chainhydrophobic part of the surfactant binds drug and at least one of anoil, a fatty acid and a lipid tightly, while the hydrophilic part of thesurfactant binds well with the water-soluble small molecules.

The surfactants in the mixture or the combination include all of thesurfactants described herein for use in embodiments of the invention.The surfactant in the mixture may be chosen from PEG fatty esters, PEGomega-3 fatty esters and alcohols, glycerol fatty esters, sorbitan fattyesters, PEG glyceryl fatty esters, PEG sorbitan fatty esters, sugarfatty esters, PEG sugar esters, Tween 20, Tween 40, Tween 60, Tween 80,p-isononylphenoxypolyglycidol, PEG laurate, PEG oleate, PEG stearate,PEG glyceryl laurate, PEG glyceryl oleate, PEG glyceryl stearate,polyglyceryl laurate, plyglyceryl oleate, polyglyceryl myristate,polyglyceryl palmitate, polyglyceryl-6 laurate, plyglyceryl-6 oleate,polyglyceryl-6 myristate, polyglyceryl-6 palmitate, polyglyceryl-10laurate, plyglyceryl-10 oleate, polyglyceryl-10 myristate,polyglyceryl-10 palmitate, PEG sorbitan monolaurate, PEG sorbitanmonolaurate, PEG sorbitan monooleate, PEG sorbitan stearate, PEG oleylether, PEG laurayl ether, octoxynol, monoxynol, tyloxapol, sucrosemonopalmitate, sucrose monolaurate, decanoyl-N-methylglucamide,n-decyl-β-D-glucopyranoside, n-decyl-β-D-maltopyranoside,n-dodecyl-β-D-glucopyranoside, n-dodecyl-β-D-maltoside,heptanoyl-N-methylglucamide, n-heptyl-β-D-glucopyranoside,n-heptyl-β-D-thioglucoside, n-hexyl-β-D-glucopyranoside,nonanoyl-N-methylglucamide, n-noyl-β-D-glucopyranoside,octanoyl-N-methylglucamide, n-octyl-β-D-glucopyranoside,octyl-β-D-thioglucopyranoside and their derivatives.

The chemical compound with one or more hydroxyl, amine, carbonyl,carboxyl, or ester moieties in the mixture or the combination includeall of the chemical compounds with one or more hydroxyl, amine,carbonyl, carboxyl, or ester moieties described in embodiments of theinvention. The chemical compound with one or more hydroxyl, amine,carbonyl, carboxyl, or ester moieties in the mixture has at least onehydroxyl group in one of the embodiments in the invention. In oneembodiment, more than four hydroxyl groups are preferred. The chemicalcompound with one or more hydroxyl, amine, carbonyl, carboxyl, or estermoieties in the mixture is chosen from L-ascorbic acid and its salt,D-glucoascorbic acid and its salt, tromethamine, triethanolamine,diethanolamine, meglumine, glucamine, amine alcohols, glucoheptonicacid, glucomic acid, hydroxyl ketone, hydroxyl lactone, gluconolactone,glucoheptonolactone, glucooctanoic lactone, gulonic acid lactone,mannoic lactone, ribonic acid lactone, lactobionic acid, glucosamine,glutamic acid, benzyl alcohol, benzoic acid, hydroxybenzoic acid, propyl4-hydroxybenzoate, lysine acetate salt, gentisic acid, lactobionic acid,lactitol, sorbitol, glucose, ribose, arabinose, lyxose, xylose,fructose, mannose, glucitol, sugars, sugar phosphates, glucopyranosephosphate, sugar sulphates, sinapic acid, vanillic acid, vanillin,methyl paraben, propyl paraben, diethylene glycol, triethylene glycol,tetraethylene glycol, xylitol, 2-ethoxyethanol, sugars, galactose,glucose, mannose, xylose, sucrose, lactose, maltose, cyclodextrin,sorbitol, (2-hydroxypropyl)-cyclodextrin, acetaminophen, ibuprofen,retinoic acid, lysine acetate, gentisic acid, catechin, catechingallate, tiletamine, ketamine, propofol, lactic acids, acetic acid,salts of any organic acid and amine described above, polyglycidol,glycerols, and derivatives thereof.

Preferred hydrophilic additives include p-isononylphenoxypolyglycidol,PEG glyceryl oleate, PEG glyceryl stearate, polyglyceryl laurate,plyglyceryl oleate, polyglyceryl myristate, polyglyceryl palmitate,polyglyceryl-6 laurate, plyglyceryl-6 oleate, polyglyceryl-6 myristate,polyglyceryl-6 palmitate, polyglyceryl-10 laurate, plyglyceryl-10oleate, polyglyceryl-10 myristate, polyglyceryl-10 palmitate, PEGsorbitan monolaurate, PEG sorbitan monolaurate, PEG sorbitan monooleate,PEG sorbitan stearate, octoxynol, monoxynol, tyloxapol, sucrosemonopalmitate, sucrose monolaurate, decanoyl-N-methylglucamide,n-decyl-β-D-glucopyranoside, n-decyl-β-D-maltopyranoside,n-dodecyl-β-D-glucopyranoside, n-dodecyl-β-D-maltoside,heptanoyl-N-methylglucamide, n-heptyl-β-D-glucopyranoside,n-heptyl-β-D-thioglucoside, n-hexyl-β-D-glucopyranoside,nonanoyl-N-methylglucamide, n-noyl-β-D-glucopyranoside,octanoyl-N-methylglucamide, n-octyl-β-D-glucopyranoside,octyl-β-D-thioglucopyranoside; cystine, tyrosine, tryptophan, leucine,isoleucine, phenylalanine, asparagine, aspartic acid, glutamic acid, andmethionine (amino acids); cetotiamine; cycothiamine, dexpanthenol,niacinamide, nicotinic acid and its salt, pyridoxal 5-phosphate,nicotinamide ascorbate, riboflavin, riboflavin phosphate, thiamine,folic acid, menadiol diphosphate, menadione sodium bisulfite,menadoxime, vitamin B12, vitamin K5, vitamin K6, vitamin K6, and vitaminU (vitamins); albumin, immunoglobulins, caseins, hemoglobins, lysozymes,immunoglobins, a-2-macroglobulin, fibronectins, vitronectins,firbinogens, lipases, benzalkonium chloride, benzethonium chloride,docecyl trimethyl ammonium bromide, sodium docecylsulfates, dialkylmethylbenzyl ammonium chloride, and dialkylesters of sodiumsulfonsuccinic acid, L-ascorbic acid and its salt, D-glucoascorbic acidand its salt, tromethamine, triethanolamine, diethanolamine, meglumine,glucamine, amine alcohols, glucoheptonic acid, glucomic acid, hydroxylketone, hydroxyl lactone, gluconolactone, glucoheptonolactone,glucooctanoic lactone, gulonic acid lactone, mannoic lactone, ribonicacid lactone, lactobionic acid, glucosamine, glutamic acid, benzylalcohol, benzoic acid, hydroxybenzoic acid, propyl 4-hydroxybenzoate,lysine acetate salt, gentisic acid, lactobionic acid, lactitol, sinapicacid, vanillic acid, vanillin, methyl paraben, propyl paraben, sorbitol,cyclodextrin, (2-hydroxypropyl)-cyclodextrin, acetaminophen, ibuprofen,retinoic acid, lysine acetate, gentisic acid, catechin, catechingallate, tiletamine, ketamine, propofol, lactic acids, acetic acid,salts of any organic acid and amine described above, polyglycidol,glycerols, and derivatives thereof. (chemical compounds with one or morehydroxyl, amino, carbonyl, carboxyl, or ester moieties). Some of theseadditives are both water-soluble and organic solvent-soluble. They havegood adhesive properties and adhere to the surface of polyamide medicaldevices, such as balloon catheters. They may therefore be used in theadherent layer, top layer, and/or in the drug layer of embodiments ofthe present invention. The aromatic and aliphatic groups increase thesolubility of water insoluble drugs in the coating solution, and thepolar groups of alcohols and acids accelerate drug release from thedevice and drug permeation into tissue.

Other preferred additives according to embodiments of the inventioninclude the combination of an amino alcohol and an organic acid.Examples are lysine/glutamic acid, lysine acetate, lactobionicacid/meglumine, lactobionic acid/tromethanemine, lactobionicacid/diethanolamine, lactic acid/meglumine, lactic acid/tromethanemine,lactic acid/diethanolamine, gentisic acid/meglumine, gentisicacid/tromethanemine, gensitic acid/diethanolamine, vanillicacid/meglumine, vanillic acid/tromethanemine, vanillicacid/diethanolamine, benzoic acid/meglumine, benzoicacid/tromethanemine, benzoic acid/diethanolamine, acetic acid/meglumine,acetic acid/tromethanemine, and acetic acid/diethanolamine.

Other preferred additives according to embodiments of the inventioninclude hydroxyl ketone, hydroxyl lactone, hydroxyl acid, hydroxylester, and hydroxyl amide. Examples are gluconolactone,D-glucoheptono-1,4-lactone, glucooctanoic lactone, gulonic acid lactone,mannoic lactone, erythronic acid lactone, ribonic acid lactone,glucuronic acid, gluconic acid, gentisic acid, lactobionic acid, lacticacid, acetaminophen, vanillic acid, sinapic acid, hydroxybenzoic acid,methyl paraben, propyl paraben, and derivatives thereof.

Other preferred additives that may be useful in embodiments of thepresent invention include riboflavin, riboflavin-phosphate sodium,Vitamin D3, folic acid (vitamin B9), vitamin 12,diethylenetriaminepentaacetic acid dianhydride,ethylenediaminetetraacetic dianhydride, maleic acid and anhydride,succinic acid and anhydride, diglycolic anhydride, glutaric anhydride,L-ascorbic acid, thiamine, nicotinamide, nicotinic acid,2-pyrrolidone-5-carboxylic acid, cystine, tyrosine, tryptophan, leucine,isoleucine, phenylalanine, asparagine, aspartic acid, glutamic acid, andmethionine.

From a structural point of view, these additives share structuralsimilarities and are compatible with water insoluble drugs (such aspaclitaxel and rapamycin). They often contain double bonds such as C═C,C═N, C═O in aromatic or aliphatic structures. These additives alsocontain amine, alcohol, ester, amide, anhydride, carboxylic acid, and/orhydroxyl groups. They may have an affinity to the therapeutic byhydrogen bonding and/or by charge and/or by van der Waals interactions.They are also useful in the top layer in the coating. Compoundscontaining one or more hydroxyl, carboxyl, or amine groups, for example,are especially useful as additives since they facilitate drug releasefrom the device surface and easily displace water next to the polar headgroups and surface proteins of cell membranes and may thereby removethis barrier to hydrophobic drug permeability. They accelerate movementof a hydrophobic drug off the balloon to the lipid layer of cellmembranes and tissues for which it has very high affinity. They may alsocarry or accelerate the movement of drug off the balloon into moreaqueous environments such as the interstitial space, for example, ofvascular tissues that have been injured by balloon angioplasty or stentexpansion. Additives such as polyglyceryl fatty esters, ascorbic esterof fatty acids, sugar esters, alcohols and ethers of fatty acids havefatty chains that can integrate into the lipid structure of targettissue membranes, carrying drug to lipid structures. Some of the aminoacids, vitamins and organic acids have aromatic C═N groups as well asamino, hydroxyl, and carboxylic components to their structure. They havestructural parts that can bind or complex with hydrophobic drug, such aspaclitaxel or rapamycin, and they also have structural parts thatfacilitate tissue penetration by removing barriers between hydrophobicdrug and lipid structure of cell membranes.

For example, isononylphenylpolyglycidol (Olin-10 G and Surfactant-10G),PEG glyceryl monooleate, sorbitan monolaurate (Arlacel 20), sorbitanmonopalmitate (Span-40), sorbitan monooleate (Span-80), sorbitanmonostearate, polyglyceryl-10 oleate, polyglyceryl-10 laurate,polyglyceryl-10 palmitate, and polyglyceryl-10 stearate all have morethan four hydroxyl groups in their hydrophilic part. These hydroxylgroups have very good affinity for the vessel wall and can displacehydrogen-bound water molecules. At the same time, they have long chainsof fatty acid, alcohol, ether and ester that can both complex withhydrophobic drug and integrate into the lipid structure of the cellmembranes to form the part of the lipid structure. This deformation orloosening of the lipid membrane of target cells may further acceleratepermeation of hydrophobic drug into tissue.

For another example, L-ascorbic acid, thiamine, maleic acids,niacinamide, and 2-pyrrolidone-5-carboxylic acid all have a very highwater and ethanol solubility and a low molecular weight and small size.They also have structural components including aromatic C═N, amino,hydroxyl, and carboxylic groups. These structures have very goodcompatibility with paclitaxel and rapamycin and can increase thesolubility of these water-insoluble drugs in water and enhance theirabsorption into tissues. However, they often have poor adhesion to thesurface of medical devices. They are therefore preferably used incombination with other additives in the drug layer and top layer wherethey are useful to enhance drug absorption. Vitamin D2 and D3 areespecially useful because they themselves have anti-restenotic effectsand reduce thrombosis, especially when used in combination withpaclitaxel.

In one embodiment, the concentration density of the at least onetherapeutic agent applied to the surface of the medical device is fromabout 1 to 20 μg/mm², or more preferably from about 2 to 6 μg/mm². Inone embodiment, the concentration of the at least one additive appliedto the surface of the medical device is from about 1 to 20 μg/mm². Inone embodiment, the concentration of the at least one of an oil, a fattyacid, and a lipid applied to the surface of the medical device is fromabout 1 to 20 μg/mm². The ratio of additives to drug by weight in thecoating layer in embodiments of the present invention is about 20 to0.05, preferably about 10 to 0.5, or more preferably about 5 to 0.8.

The relative amount of the therapeutic agent, at least one of an oil, afatty acid and a lipid, and the additive in the coating layer may varydepending on applicable circumstances. The optimal amount of theadditive can depend upon, for example, the particular therapeutic agent,the at least one of an oil, a lipid, and a fatty acid, and the additiveselected, the critical micelle concentration of the surface modifier,the hydrophilic-lipophilic-balance (HLB) of a surfactant or anadditive's the octonol-water partition coefficient (P), the meltingpoint of the additive, the water solubility of the additive and/ortherapeutic agent, the surface tension of water solutions of the surfacemodifier, etc. The oils, fatty acids, and lipids of the presentinvention are not formed into miscelles, liposomes or particles, andthey do not encapsulate the therapeutic agent in particles.

Other considerations will further inform the choice of specificproportions of different additives, oils, lipids, and fatty acids. Theseconsiderations include the degree of bioacceptability of the additivesand the desired dosage of hydrophobic therapeutic agent to be provided.

Therapeutic Agent

The drugs or biologically active materials, which can be used inembodiments of the present invention, can be any therapeutic agent orsubstance. The drugs can be of various physical states, e.g., moleculardistribution, crystal forms or cluster forms. Examples of drugs that areespecially useful in embodiments of the present invention are lipophilicsubstantially water insoluble drugs, such as paclitaxel, rapamycin,daunorubicin, doxorubicin, lapachone, vitamin D2 and D3 and analoguesand derivatives thereof. These drugs are especially suitable for use ina coating on a balloon catheter used to treat tissue of the vasculature.

Other drugs that may be useful in embodiments of the present inventioninclude, without limitation, glucocorticoids (e.g., dexamethasone,betamethasone), hirudin, angiopeptin, aspirin, growth factors, antisenseagents, anti-cancer agents, anti-proliferative agents, oligonucleotides,and, more generally, anti-platelet agents, anti-coagulant agents,anti-mitotic agents, antioxidants, anti-metabolite agents,anti-chemotactic, and anti-inflammatory agents.

Also useful in embodiments of the present invention are polynucleotides,antisense, RNAi, or siRNA, for example, that inhibit inflammation and/orsmooth muscle cell or fibroblast proliferation.

Anti-platelet agents can include drugs such as aspirin and dipyridamole.Aspirin is classified as an analgesic, antipyretic, anti-inflammatoryand anti-platelet drug. Dipyridamole is a drug similar to aspirin inthat it has anti-platelet characteristics. Dipyridamole is alsoclassified as a coronary vasodilator. Anti-coagulant agents for use inembodiments of the present invention can include drugs such as heparin,protamine, hirudin and tick anticoagulant protein. Anti-oxidant agentscan include probucol. Anti-proliferative agents can include drugs suchas amlodipine and doxazosin. Anti-mitotic agents and anti-metaboliteagents that can be used in embodiments of the present invention includedrugs such as methotrexate, azathioprine, vincristine, vinblastine,5-fluorouracil, adriamycin, and mutamycin. Antibiotic agents for use inembodiments of the present invention include penicillin, cefoxitin,oxacillin, tobramycin, and gentamicin. Suitable antioxidants for use inembodiments of the present invention include probucol. Additionally,genes or nucleic acids, or portions thereof can be used as thetherapeutic agent in embodiments of the present invention. Furthermore,collagen-synthesis inhibitors, such as tranilast, can be used as atherapeutic agent in embodiments of the present invention.

Photosensitizing agents for photodynamic or radiation therapy, includingvarious porphyrin compounds such as porfimer, for example, are alsouseful as drugs in embodiments of the present invention.

Drugs for use in embodiments of the present invention also includeeverolimus, somatostatin, tacrolimus, roxithromycin, dunaimycin,ascomycin, bafilomycin, erythromycin, midecamycin, josamycin,concanamycin, clarithromycin, troleandomycin, folimycin, cerivastatin,simvastatin, lovastatin, fluvastatin, rosuvastatin, atorvastatin,pravastatin, pitavastatin, vinblastine, vincristine, vindesine,vinorelbine, etoposide, teniposide, nimustine, carmustine, lomustine,cyclophosphamide, 4-hydroxycyclophosphamide, estramustine, melphalan,ifosfamide, trofosfamide, chlorambucil, bendamustine, dacarbazine,busulfan, procarbazine, treosulfan, temozolomide, thiotepa,daunorubicin, doxorubicin, aclarubicin, epirubicin, mitoxantrone,idarubicin, bleomycin, mitomycin, dactinomycin, methotrexate,fludarabine, fludarabine-5′-dihydrogenphosphate, cladribine,mercaptopurine, thioguanine, cytarabine, fluorouracil, gemcitabine,capecitabine, docetaxel, carboplatin, cisplatin, oxaliplatin, amsacrine,irinotecan, topotecan, hydroxycarbamide, miltefosine, pentostatin,aldesleukin, tretinoin, asparaginase, pegaspargase, anastrozole,exemestane, letrozole, formestane, aminoglutethimide, adriamycin,azithromycin, spiramycin, cepharantin, smc proliferation inhibitor-2w,epothilone A and B, mitoxantrone, azathioprine, mycophenolatmofetil,c-myc-antisense, b-myc-antisense, betulinic acid, camptothecin,lapachol, beta.-lapachone, podophyllotoxin, betulin, podophyllic acid2-ethylhydrazide, molgramostim (rhuGM-CSF), peginterferon a-2b,lenograstim (r-HuG-CSF), filgrastim, macrogol, dacarbazine, basiliximab,daclizumab, selectin (cytokine antagonist), CETP inhibitor, cadherines,cytokinin inhibitors, COX-2 inhibitor, NFkB, angiopeptin, ciprofloxacin,camptothecin, fluroblastin, monoclonal antibodies, which inhibit themuscle cell proliferation, bFGF antagonists, probucol, prostaglandins,1,11-dimethoxycanthin-6-one, 1-hydroxy-11-methoxycanthin-6-one,scopoletin, colchicine, NO donors such as pentaerythritol tetranitrateand syndnoeimines, S-nitrosoderivatives, tamoxifen, staurosporine,beta.-estradiol, a-estradiol, estriol, estrone, ethinylestradiol,fosfestrol, medroxyprogesterone, estradiol cypionates, estradiolbenzoates, tranilast, kamebakaurin and other terpenoids, which areapplied in the therapy of cancer, verapamil, tyrosine kinase inhibitors(tyrphostines), cyclosporine A, 6-a-hydroxy-paclitaxel, baccatin,taxotere and other macrocyclic oligomers of carbon suboxide (MCS) andderivatives thereof, mofebutazone, acemetacin, diclofenac, lonazolac,dapsone, o-carbamoylphenoxyacetic acid, lidocaine, ketoprofen, mefenamicacid, piroxicam, meloxicam, chloroquine phosphate, penicillamine,hydroxychloroquine, auranofin, sodium aurothiomalate, oxaceprol,celecoxib, .beta.-sitosterin, ademetionine, myrtecaine, polidocanol,nonivamide, levomenthol, benzocaine, aescin, ellipticine, D-24851(Calbiochem), colcemid, cytochalasin A-E, indanocine, nocodazole, S 100protein, bacitracin, vitronectin receptor antagonists, azelastine,guanidyl cyclase stimulator tissue inhibitor of metal proteinase-1 and-2, free nucleic acids, nucleic acids incorporated into virustransmitters, DNA and RNA fragments, plasminogen activator inhibitor-1,plasminogen activator inhibitor-2, antisense oligonucleotides, VEGFinhibitors, IGF-1, active agents from the group of antibiotics such ascefadroxil, cefazolin, cefaclor, cefotaxim, tobramycin, gentamycin,penicillins such as dicloxacillin, oxacillin, sulfonamides,metronidazol, antithrombotics such as argatroban, aspirin, abciximab,synthetic antithrombin, bivalirudin, coumadin, enoxaparin, desulphatedand N-reacetylated heparin, tissue plasminogen activator, GpIIb/IIIaplatelet membrane receptor, factor Xa inhibitor antibody, heparin,hirudin, r-hirudin, PPACK, protamin, prourokinase, streptokinase,warfarin, urokinase, vasodilators such as dipyramidole, trapidil,nitroprussides, PDGF antagonists such as triazolopyrimidine and seramin,ACE inhibitors such as captopril, cilazapril, lisinopril, enalapril,losartan, thiol protease inhibitors, prostacyclin, vapiprost, interferona, .beta and y, histamine antagonists, serotonin blockers, apoptosisinhibitors, apoptosis regulators such as p65 NF-kB or Bcl-xL antisenseoligonucleotides, halofuginone, nifedipine, tranilast, molsidomine, teapolyphenols, epicatechin gallate, epigallocatechin gallate, Boswellicacids and derivatives thereof, leflunomide, anakinra, etanercept,sulfasalazine, etoposide, dicloxacillin, tetracycline, triamcinolone,mutamycin, procainamide, retinoic acid, quinidine, disopyramide,flecainide, propafenone, sotalol, amidorone, natural and syntheticallyobtained steroids such as bryophyllin A, inotodiol, maquiroside A,ghalakinoside, mansonine, strebloside, hydrocortisone, betamethasone,dexamethasone, non-steroidal substances (NSAIDS) such as fenoprofen,ibuprofen, indomethacin, naproxen, phenylbutazone and other antiviralagents such as acyclovir, ganciclovir and zidovudine, antimycotics suchas clotrimazole, flucytosine, griseofulvin, ketoconazole, miconazole,nystatin, terbinafine, antiprozoal agents such as chloroquine,mefloquine, quinine, moreover natural terpenoids such as hippocaesculin,barringtogenol-C21-angelate, 14-dehydroagrostistachin, agroskerin,agrostistachin, 17-hydroxyagrostistachin, ovatodiolids,4,7-oxycycloanisomelic acid, baccharinoids B1, B2, B3 and B7,tubeimoside, bruceanol A, B and C, bruceantinoside C, yadanziosides Nand P, isodeoxyelephantopin, tomenphantopin A and B, coronarin A, B, Cand D, ursolic acid, hyptatic acid A, zeorin, iso-iridogermanal,maytenfoliol, effusantin A, excisanin A and B, longikaurin B,sculponeatin C, kamebaunin, leukamenin A and B,13,18-dehydro-6-a-senecioyloxychaparrin, taxamairin A and B, regenilol,triptolide, moreover cymarin, apocymarin, aristolochic acid, anopterin,hydroxyanopterin, anemonin, protoanemonin, berberine, cheliburinchloride, cictoxin, sinococuline, bombrestatin A and B, cudraisoflavoneA, curcumin, dihydronitidine, nitidine chloride,12-beta-hydroxypregnadien-3,20-dione, bilobol, ginkgol, ginkgolic acid,helenalin, indicine, indicine-N-oxide, lasiocarpine, inotodiol,glycoside 1a, podophyllotoxin, justicidin A and B, larreatin,malloterin, mallotochromanol, isobutyrylmallotochromanol, maquiroside A,marchantin A, maytansine, lycoridicin, margetine, pancratistatin,liriodenine, bisparthenolidine, oxoushinsunine, aristolactam-AII,bisparthenolidine, periplocoside A, ghalakinoside, ursolic acid,deoxypsorospermin, psychorubin, ricin A, sanguinarine, manwu wheat acid,methylsorbifolin, sphatheliachromen, stizophyllin, mansonine,strebloside, akagerine, dihydrousambarensine, hydroxyusambarine,strychnopentamine, strychnophylline, usambarine, usambarensine,berberine, liriodenine, oxoushinsunine, daphnoretin, lariciresinol,methoxylariciresinol, syringaresinol, umbelliferon, afromoson,acetylvismione B, desacetylvismione A, and vismione A and B.

A combination of drugs can also be used in embodiments of the presentinvention. Some of the combinations have additive effects because theyhave a different mechanism, such as paclitaxel and rapamycin, paclitaxeland active vitamin D, paclitaxel and lapachone, rapamycin and activevitamin D, rapamycin and lapachone. Because of the additive effects, thedose of the drug can be reduced as well. These combinations may reducecomplications from using a high dose of the drug.

Adherent Layer

The adherent layer, which is an optional layer underlying the drugcoating layer, improves the adherence of the drug coating layer to theexterior surface of the medical device and protects coating integrity.If drug and additive differ in their adherence to the medical device,the adherent layer may prevent differential loss (during transit) orelution (at the target site) of drug layer components in order tomaintain consistent drug-to-additive, drug-to-oil, lipid, or fattyacid-ratio, or drug-to-drug ratio in the drug layer and therapeuticdelivery at the target site of intervention. Furthermore, the adherentlayer may function to facilitate release of coating layer componentswhich otherwise might adhere too strongly to the device for elutionduring brief contact with tissues at the target site. For example, inthe case where a particular drug binds the medical device tightly, morehydrophilic components are incorporated into the adherent layer in orderto decrease affinity of the drug to the device surface.

The adherent layer may also comprise one or more of an oil, a fattyacid, and a lipid and the additives previously described, or othercomponents, in order to maintain the integrity and adherence of thecoating layer to the device and to facilitate both adherence of drug andadditive components during transit and rapid elution during deploymentat the site of therapeutic intervention.

Top Layer

In order to further protect the integrity of the drug layer, an optionaltop layer may be applied to prevent loss of drug during transit throughtortuous anatomy to the target site or during the initial expansion ofthe device before the coating makes direct contact with target tissue.The top layer may release slowly in the body lumen while protecting thedrug layer. The top layer will erode more slowly if it is comprised ofmore hydrophobic, high molecular weight additives. Surfactants areexamples of more hydrophobic structures with long fatty chains, such asTween 80, Tween 20 and polyglyceryl oleate. High molecular weightadditives include polyethylene oxide, polyethylene glycol, and polyvinylpyrrolidone. Hydrophobic drug itself can act as a top layer component.For example, paclitaxel or rapamycin are hydrophobic. They can be usedin the top layer. On the other hand, the top layer cannot erode tooslowly or it might actually slow the release of drug during deploymentat the target site. Other additives useful in the top coat includeadditives that strongly interact with drug or with the coating layer,such as L-ascorbic acid and its salt, D-glucoascorbic acid and its salt,tromethamine, triethanolamine, diethanolamine, meglumine, glucamine,amine alcohols, glucoheptonic acid, glucomic acid, gluconolactone,glucosamine, glutamic acid, benzyl alcohol, benzoic acid, hydroxybenzoicacid, propyl 4-hydroxybenzoate, lysine acetate salt, gentisic acid,lactobionic acid, lactitol, sinapic acid, vanillic acid, vanillin,methyl paraben, propyl paraben, cyclodextrin,(2-hydroxypropyl)-cyclodextrin, acetaminophen, ibuprofen, retinoic acid,lysine acetate, gentisic acid, catechin, catechin gallate, tiletamine,ketamine, propofol, lactic acids, acetic acid, salts of any organic acidand amine described above, polyglycidol, glycerols, multiglycerols, andderivatives thereof.

Solvents

Solvents for preparing of the coating layer may include, as examples,any combination of one or more of the following: (a) water, (b) alkanessuch as hexane, octane, cyclohexane, and heptane, (c) aromatic solventssuch as benzene, toluene, and xylene, (d) alcohols such as ethanol,propanol, and isopropanol, diethylamide, ethylene glycol monoethylether, Trascutol, and benzyl alcohol (e) ethers such as dioxane,dimethyl ether and tetrahydrofuran, (f) esters/acetates such as ethylacetate and isobutyl acetate, (g) ketones such as acetone, acetonitrile,diethyl ketone, and methyl ethyl ketone, and (h) mixture of water andorganic solvents such as water/ethanol, water/acetone, water/methanol,water/tetrahydrofuran.

Organic solvents, such as short-chained alcohol, dioxane,tetrahydrofuran, dimethylformamide, acetonitrile, dimethylsulfoxide,etc., are particularly useful and preferred solvents in embodiments ofthe present invention because these organic solvents generally disruptcollodial aggregates and co-solubilize all the components in the coatingsolution.

The therapeutic agent, the at least one of an oil, a fatty acid and alipid, and the additive or additives may be dispersed in, solubilized,or otherwise mixed in the solvent. The weight percent of drug, at leastone of an oil, a fatty acid and a lipid, and the additive in the solventmay be in the range of 0.1-80% by weight, preferably 2-20% by weight.

In one embodiment, the ratio of the therapeutic agent to the at leastone of an oil, a fatty acid, and a lipid is greater than 0.3. In oneembodiment, the ratio of drug to additive is greater than 8 mol %. Inone embodiment, the ratio of drug to the at least one of an oil, a fattyacid, and a lipid is greater than 10 mol %. All other things beingequal, a higher ratio of drug to the at least one oil, fatty acid, andlipid is advantageous, since it is the drug that delivers thetherapeutic effect upon delivery to target tissue.

Another embodiment of the invention relates to a method for preparing amedical device, particularly, for example, a balloon catheter or astent. First, a coating solution or suspension comprising at least onesolvent, at least one therapeutic agent, at least one of an oil, a fattyacid and a lipid, and at least one additive is prepared. In at least oneembodiment, the coating solution or suspension includes only thesecomponents. The content of the therapeutic agent in the coating solutioncan be from 0.5-50% by weight based on the total weight of the solution.The content of the additive, or the at least one of an oil, a fattyacid, and a lipid in the coating solution can be from 1-45% by weight, 1to 40% by weight, or from 1-15% by weight based on the total weight ofthe solution. The amount of solvent used depends on the coating processand viscosity. It will affect the uniformity of the coating but will beevaporated.

In other embodiments, two or more solvents, two or more therapeuticagents, two or more of the at least one of an oil, a fatty acid, and alipid, and/or two or more additives may be used in the coating solution.

Various techniques may be used for applying a coating solution to amedical device such as casting, spinning, spraying, dipping (immersing),ink jet printing, electrostatic techniques, and combinations of theseprocesses. Choosing an application technique principally depends on theviscosity and surface tension of the solution. In embodiments of thepresent invention, dipping and spraying are preferred because it makesit easier to control the uniformity of the thickness of the coatinglayer as well as the concentration of the therapeutic agent applied tothe medical device. Regardless of whether the coating is applied byspraying or by dipping or by another method or combination of methods,each layer is usually deposited on the medical device in multipleapplication steps in order to control the uniformity and the amount oftherapeutic substance and additive applied to the medical device.

Each applied layer is from about 0.1 microns to 15 microns in thickness.The total number of layers applied to the medical device is in a rangeof from about 2 to 50. The total thickness of the coating is from about2 to 200 microns.

As discussed above, spraying and dipping are particularly useful coatingtechniques for use in embodiments of the present invention. In aspraying technique, a coating solution or suspension of an embodiment ofthe present invention is prepared and then transferred to an applicationdevice for applying the coating solution or suspension to a ballooncatheter.

An application device that may be used is a paint jar attached to an airbrush, such as a Badger Model 150, supplied with a source of pressurizedair through a regulator (Norgren, 0-160 psi). When using such anapplication device, once the brush hose is attached to the source ofcompressed air downstream of the regulator, the air is applied. Thepressure is adjusted to approximately 15-25 psi and the nozzle conditionchecked by depressing the trigger.

Prior to spraying, both ends of the relaxed balloon are fastened to thefixture by two resilient retainers, i.e., alligator clips, and thedistance between the clips is adjusted so that the balloon remained in adeflated, folded, or an inflated or partially inflated, unfoldedcondition. The rotor is then energized and the spin speed adjusted tothe desired coating speed, about 40 rpm.

With the balloon rotating in a substantially horizontal plane, the spraynozzle is adjusted so that the distance from the nozzle to the balloonis about 1-4 inches. First, the coating solution is sprayedsubstantially horizontally with the brush being directed along theballoon from the distal end of the balloon to the proximal end and thenfrom the proximal end to the distal end in a sweeping motion at a speedsuch that one spray cycle occurred in about three balloon rotations. Theballoon is repeatedly sprayed with the coating solution, followed bydrying, until an effective amount of the drug is deposited on theballoon.

In one embodiment of the present invention, the balloon is inflated orpartially inflated, the coating solution is applied to the inflatedballoon, for example by spraying, and then the balloon is deflated andfolded before drying. Drying may be performed under vacuum.

It should be understood that this description of an application device,fixture, and spraying technique is exemplary only. Any other suitablespraying or other technique may be used for coating the medical device,particularly for coating the balloon of a balloon catheter or stentdelivery system or stent.

After the medical device is sprayed with the coating solution, thecoated balloon is subjected to a drying in which the solvent in thecoating solution is evaporated. This produces a coating matrix on theballoon containing the therapeutic agent. One example of a dryingtechnique is placing a coated balloon into an oven at approximately 20°C. or higher for approximately 24 hours. Any other suitable method ofdrying the coating solution may be used. The time and temperature mayvary with particular additives and therapeutic agents.

Optional Post Treatment

After depositing the drug-additive containing layer on the device ofcertain embodiments of the present invention, dimethyl sulfoxide (DMSO)or other solvent may be applied, by dip or spray or other method, to thefinished surface of the coating. DMSO readily dissolves drugs and easilypenetrates membranes and may enhance tissue absorption.

It is contemplated that the medical devices of embodiments of thepresent invention have applicability for treating blockages andocclusions of any body passageways, including, among others, thevasculature, including coronary, peripheral, and cerebral vasculature,the gastrointestinal tract, including the esophagus, stomach, smallintestine, and colon, the pulmonary airways, including the trachea,bronchi, bronchioles, the sinus, the biliary tract, the urinary tract,prostate and brain passages. They are especially suited for treatingtissue of the vasculature with, for example, a balloon catheter or astent.

Yet another embodiment of the present invention relates to a method oftreating a blood vessel. The method includes inserting a medical devicecomprising a coating into a blood vessel. The coating layer comprises atherapeutic agent, at least one of an oil, a fatty acid and a lipid, andan additive. In this embodiment, the medical device can be configured ashaving at least an expandable portion. Some examples of such devicesinclude balloon catheters, perfusion balloon catheters, an infusioncatheter such as distal perforated drug infusion catheters, a perforatedballoon, spaced double balloon, porous balloon, and weeping balloon,cutting balloon catheters, scoring balloon catheters, self-expanded andballoon expanded-stents, guide catheters, guide wires, embolicprotection devices, and various imaging devices.

As mentioned above, one example of a medical device that is particularlyuseful in the present invention is a coated balloon catheter. A ballooncatheter typically has a long, narrow, hollow tube tabbed with aminiature, deflated balloon. In embodiments of the present invention,the balloon is coated with a drug solution. Then, the balloon ismaneuvered through the cardiovascular system to the site of a blockage,occlusion, or other tissue requiring a therapeutic agent. Once in theproper position, the balloon is inflated and contacts the walls of theblood vessel and/or a blockage or occlusion. It is an object ofembodiments of the present invention to rapidly deliver drug to andfacilitate absorption by target tissue. It is advantageous toefficiently deliver drug to tissue in as brief a period of time aspossible while the device is deployed at the target site. Thetherapeutic agent is released into such tissue, for example the vesselwalls, in about 0.1 to 30 minutes, for example, or preferably about 0.1to 10 minutes, or more preferably about 0.2 to 2 minutes, or mostpreferably, about 0.1 to 1 minutes, of balloon inflation time pressingthe drug coating into contact with diseased vascular tissue.

Further, the balloon catheter may be used to treat vasculartissue/disease alone or in combination with other methods for treatingthe vasculature, for example, photodynamic therapy or atherectomy.Atherectomy is a procedure to remove plaque from arteries. Specifically,atherectomy removes plaque from peripheral and coronary arteries. Themedical device used for peripheral or coronary atherectomy may be alaser catheter or a rotablator or a direct atherectomy device on the endof a catheter. The catheter is inserted into the body and advancedthrough an artery to the area of narrowing. After the atherectomy hasremoved some of the plaque, balloon angioplasty using the coated balloonof embodiments of the present invention may be performed. In addition,stenting may be performed thereafter, or simultaneous with expansion ofthe coated balloon as described above. Photodynamic therapy is aprocedure where light or irradiated energy is used to kill target cellsin a patient. A light-activated photosensitizing drug may be deliveredto specific areas of tissue by embodiments of the present invention. Atargeted light or radiation source selectively activates the drug toproduce a cytotoxic response and mediate a therapeuticanti-proliferative effect.

In some of the embodiments of drug-containing coatings and layersaccording to the present invention, however, the coating or layer doesnot include a polymer. And, furthermore, the therapeutic agent is notencapsulated in polymer particles, micelles, or liposomes. As describedabove, such formulations have significant disadvantages and can inhibitthe intended efficient, rapid release and tissue penetration of theagent, especially in the environment of diseased tissue of thevasculature.

Although various embodiments are specifically illustrated and describedherein, it will be appreciated that modifications and variations of thepresent invention are covered by the above teachings and are within thepurview of the appended claims without departing from the spirit andintended scope of the invention.

Other than the operating examples, or where otherwise indicated, allnumbers expressing quantities of components in a layer, reactionconditions, and so forth used in the specification and claims are to beunderstood as being modified in all instances by the term “about.”Accordingly, unless otherwise indicated to the contrary, the numericalparameters set forth in this specification and attached claims areapproximations that may vary depending upon the desired propertiessought to be obtained by the present disclosure.

Preparation

The medical device and the coating layers of embodiments of the presentinvention can be made according to various methods. For example, thecoating solution can be prepared by dispersing, dissolving, diffusing,or otherwise mixing all the ingredients, such as a therapeutic agent, atleast one of an oil, a fatty acid and a lipid, an additive, and asolvent, simultaneously together. Also, the coating solution can beprepared by sequentially adding each component based on solubility orany other parameters. For example, the coating solution can be preparedby first adding the therapeutic agent and the at least one of an oil, afatty acid, and a lipid to the solvent and then adding the additive.Alternatively, the additive can be added to the solvent first and thenthe therapeutic agent, oil, fatty acid, or lipid can be later added. Ifthe solvent used does not sufficiently dissolve the drug, it ispreferable to first add the additive to the solvent, then the drug,since the additive will increase drug solubility in the solvent.

In some embodiments, encapsulating liposomes or particles are not formedbecause the coating solution or dispersion in organic solvent is coateddirectly onto the medical device, without first drying or evaporating orotherwise removing the organic solvent. That is, there is noreconstitution in aqueous solution of a dried lipid cake or film thatmight be formed by removal of organic solvent, as is typically done formanufacture of liposomes. Rather, the coating solution or dispersion inorganic solvent is coated on the balloon and then dried.

EXAMPLES

The following examples include embodiments of medical devices andcoating layers within the scope of the present invention. While thefollowing examples are considered to embody the present invention, theexamples should not be interpreted as limitations upon the presentinvention.

Example 1 Preparation of Coating Solutions Formulation 1

50-100 mg (0.06-0.12 mmmole) paclitaxel, 1-1.6 ml acetone, 1-1.6 mlethanol, 0.4-1.0 ml water, 50-200 mg phosphatidylcholine, and 50-200 mggluconolactone are mixed.

Formulation 2

50-100 mg (0.06-0.12 mmmole) paclitaxel, 1-1.6 ml acetone, 1-1.6 mlethanol, 0.4-1.0 ml water, 50-200 mg phosphatidylethanolamine, and50-200 mg gluconolactone are mixed.

Formulation 3

50-100 mg (0.06-0.12 mmmole) paclitaxel, 1-1.6 ml acetone, 1-1.6 mlethanol, 0.4-1.0 ml water, 50-200 mg dimyristoylphosphatidylcholine, and50-200 mg gluconolactone are mixed.

Formulation 4

35-70 mg (0.042-0.084 mmmole) paclitaxel, 0.5-1.0 ml acetone, 0.5-1.0 mlethanol, 5-35 mg Tween 20, and 35-70 mg phosphatidylcholine are mixed.

Formulation 5

35-70 mg (0.042-0.084 mmmole) paclitaxel, 0.4-1.0 ml acetone, 0.4-1.0 mlethanol, 0.2-0.4 ml water, 35-70 mg sorbitol, and 35-70 mgphosphatidylcholine are mixed.

Formulation 6

35-70 mg (0.042-0.084 mmmole) paclitaxel, 0.4-0.8 ml acetone, 0.4-0.8 mlethanol, 0.25-0.50 ml water, 35-70 mg lactobionic acid, and 35-70 mgphosphatidylcholine are mixed.

Formulation 7

50-100 mg (0.06-0.12 mmmole) paclitaxel, 1-1.6 ml acetone, 1-1.6 mlethanol, 0.4-1.0 ml water, 50-200 mg fish oil, and 50-200 mggluconolactone are mixed.

Formulation 8

50-100 mg (0.06-0.12 mmmole) paclitaxel, 1-1.6 ml acetone, 1-1.6 mlethanol, 0.4-1.0 ml water, 50-200 mg soybean oil, and 50-200 mggluconolactone are mixed.

Formulation 9

50-100 mg (0.06-0.12 mmmole) paclitaxel, 1-1.6 ml acetone, 1-1.6 mlethanol, 0.4-1.0 ml water, 50-200 mg olive oil, and 50-200 mggluconolactone are mixed.

Formulation 10

35-70 mg (0.042-0.084 mmmole) paclitaxel, 0.5-1.0 ml acetone, 0.5-1.0 mlethanol, 5-35 mg Tween 20, and 35-70 mg tocotrienol were mixed.

Formulation 11

35-70 mg (0.042-0.084 mmmole) paclitaxel, 0.4-1.0 ml acetone, 0.4-1.0 mlethanol, 0.2-0.4 ml water, 35-70 mg sorbitol, and 35-70 mg fish oil aremixed.

Formulation 12

35-70 mg (0.042-0.084 mmmole) paclitaxel, 0.4-0.8 ml acetone, 0.4-0.8 mlethanol, 0.25-0.50 ml water, 35-70 mg lactobionic acid, and 35-70 mgeicosapentaenoic acid are mixed.

Example 2

5 PTCA balloon catheters (3 mm in diameter and 20 mm in length) arefolded with three wings under vacuum. The folded balloon under vacuum issprayed or dipped in a formulation (1-12) in example 1. The foldedballoon is then dried, sprayed or dipped again, dried again, and sprayedor dipped again until sufficient amount of drug on the balloon (3microgram per square mm) is obtained. The coated folded balloon is thenrewrapped and sterilized for animal testing.

Example 3

5 PTCA balloon catheters (3 mm in diameter and 20 mm in length) arefolded with three wings under vacuum. The folded balloon under vacuum issprayed or dipped in a formulation (1-6) in example 1. The foldedballoon is then dried, sprayed or dipped again in a formulation (7-12),dried, and sprayed or dipped again until sufficient amount of drug onthe balloon (3 microgram per square mm) is obtained. The coated foldedballoon is then rewrapped and sterilized for animal testing.

Example 4

5 PTCA balloon catheters crimped with bare metal coronary stent (3 mm indiameter and 20 mm in length) are sprayed or dipped in a formulation(1-6) in example 1. The stent delivery system is then dried, sprayed ordipped again in a formulation (7-10), dried and sprayed or dipped againuntil sufficient amount of drug on the stent and balloon (3 microgramper square mm) is obtained. The coated folded stent delivery system isthen sterilized for animal testing.

Example 5

Drug coated balloon catheters and uncoated balloon catheters (ascontrol) are inserted into coronary arteries in pigs. The balloon isover dilated (1:1.2), and the inflated balloon is held in the vessel for60 seconds to release drug and additive, then deflated and withdrawnfrom the pig. The animals are angiographed after 3 days, 31 days, 3months, 6 months, 9 months and 12 months. The amount of drug in theartery tissues of the sacrificed animal is measured after 60 minutes, 3days, 31 days, 3 months, 6 months, 9 months and 12 months.

Example 6

5 coronary stents (3 mm in diameter and 18 mm in length) are spray ordip coated with the formulation (1-12) in example 1. The stents are thendried, sprayed or dipped again, and dried again until a sufficientamount of drug on the stent (3 microgram per square mm) is obtained. Thecoated stent is then crimped on PTCA balloon catheters (3 mm indiameters and 20 mm in length). The coated stents with balloon cathetersare then sterilized for animal testing.

Example 7

The drug coated stent and uncoated stent (as control) are inserted intocoronary arteries in pigs, then the balloon is over dilated (1:1.2). Thestent is implanted and drug and additive released, and the balloon isdeflated and withdrawn from the pig. The animals are then angiographedafter 5, 30, 60 minutes, 3 days, 31 days, 3 months, 6 months, 9 monthsand 12 months. The amount of drug in the artery tissues of thesacrificed animal is measured 60 minutes, 1 day, 3 days, 31 days, 3months, 6 months, 9 months and 12 months.

Example 8

5 PTCA balloon catheters are sprayed or dipped in the formulation (1-12)in example 1, dried, and sprayed or dipped and dried again untilsufficient amount of drug on balloon is obtained (3 microgram per squaremm). A bare metal coronary stent (3 mm in diameter and 20 mm in length)is crimped on each coated balloon. The coated balloons with crimped baremetal stents are then wrapped and sterilized for animal test.

Example 9

5 PTCA balloon catheters are sprayed or dipped in a formulation (1-6) inexample 1, dried, and sprayed or dipped again in a formulation (7-12).Balloons are then dried and sprayed or dipped again until sufficientamount of drug on the balloon (3 microgram per square mm) is obtained. Abare metal coronary stent (3 mm in diameter and 20 mm in length) iscrimped on each coated balloon. The coated balloons with crimped baremetal stents are then wrapped and sterilized for animal test.

Example 10

The drug coated balloon-expandable bare metal stent of Examples 8 and 9and plain balloon-expandable bare metal stent (as control) are insertedinto coronary arteries in pigs, and the balloon is over dilated (1:1.2).Stent is implanted, and the balloon is held inflated for 60 seconds torelease drug and additive, and the balloon is deflated and withdraw fromthe pig. The animals are then angiographed after 5, 30, 60 minutes, 3days, 31 days, 3 months, 6 months, 9 months and 12 months. The amount ofdrug in the artery tissues of the sacrificed animal is measured after 60minutes, 1 day, 3 days, 31 days, 3 months, 6 months, 9 months and 12months.

Example 11

The drug coated balloon catheters and uncoated balloon catheters (ascontrol) are inserted via a bronchoscope into the pulmonary airway inpigs. The balloon was dilated, and the inflated balloon is held expandedin the lumen for 60 seconds to release drug and additive. The balloon isdeflated and withdrawn from the pig. The animals are then examinedbronchoscopically and tissues samples are taken for pathology andquantification of drug uptake after 3 days, 31 days, 3 months, 6 months,9 months and 12 months.

Example 12

The uncoated stent delivery catheters are inserted into the vascularlumen in pigs. The balloon is dilated, the stent is deployed and thedeflated balloon is then withdrawn. The pharmaceutical formulation(1-12) of example 1 (10-100 ml) are injected (about 5-15 mg drug perpig) at the site of stent implantation. The drug is then absorbed byinjuried tissue. The animals are then examined and tissues samples aretaken for pathology.

Example 13

The diseased tissue (breast cancer or prostate or atheroma or stenosis)is removed surgically from a human body. The pharmaceutical formulation1-12 of example 1 (10-100 ml) is then injected into or onto the surgicalcavities created by the surgical intervention (about 5-20 mg drug). Thelocal drug delivery included injection by long needle, guide catheters,introducer shealth, drug infusion tube and other drug deliverycatheters. The drug is then absorbed by tissue at the target site.

Example 14

6 PTCA balloon catheters (3.5 and 3.0 mm in diameter and 20 mm inlength) are inflated at 1-3 atm. The inflated balloon is loaded with aformulation (1-12) in example 1. A sufficient amount of drug on theballoon (3 microgram per square mm) is obtained. The inflated balloon isfolded, and then dried. The coated folded balloon is then rewrapped andsterilized for animal testing.

The coated PTCA balloon catheter is inserted into a target site in thecoronary vasculature (LAD, LCX and RCA) of a 25-45 pound pig. Theballoon is inflated to about 12 atm. The overstretch ratio (the ratio ofballoon diameter to vessel diameter) is about 1.15-1.20. The drug isdelivered into the target tissue during 30-60 seconds of inflation. Theballoon catheter is then deflated and is withdrawn from the animal body.The target blood vessel is harvested 0.25-24 hours after the procedure.The drug content in the target tissue and the residual drug remaining onthe balloon is analyzed by tissue extraction and HPLC.

In some of these animal studies, a stent is crimped on the drug coatedballoon catheters prior to deployment. In chronic animal tests,angiography is performed before and after all interventions and at 28-35days after the procedure. Luminal diameters are measured and late lumenloss is calculated. Late lumen loss is the difference between theminimal lumen diameter measured after a period of follow-up time(usually weeks to months after an intervention, such as angioplasty andstent placement in the case of this example) and the minimal lumendiameter measured immediately after the intervention. Restenosis may bequantified by the diameter stenosis, which is the difference between themean lumen diameters at follow-up and immediately after the proceduredivided by the mean lumen diameter immediately after the procedure.

What is claimed is:
 1. A medical device for delivering a therapeuticagent to a tissue, the medical device comprising a coating layeroverlying an exterior surface of the medical device, the coating layerconsisting essentially of: a hydrophobic therapeutic agent chosen frompaclitaxel, rapamycin, doxorubicin, beta-lapachone, vitamin D2, vitaminD3, and combinations thereof; at least one water-soluble first additiveselected from the group consisting of PEG fatty esters, gluconolactone,and combinations thereof; and at least one water-insoluble secondadditive selected from the group consisting of phosphatidylcholine,phosphatidylethanolamine, dimyristoylphosphatidylcholine, andcombinations thereof.
 2. The medical device of claim 1, wherein thetissue includes tissue of one of coronary vasculature, peripheralvasculature, cerebral vasculature, esophagus, airways, sinus, trachea,colon, biliary tract, urinary tract, prostate, and brain passages. 3.The medical device of claim 1, wherein the medical device is chosen froma laser catheter, an atherectomy device, a debulking catheter, a stent,a filter, a stent graft, a covered stent, a patch, a wire, and a valve.4. The medical device of claim 1, wherein the therapeutic agent in thecoating layer is a combination of paclitaxel and a second therapeuticagent chosen from rapamycin, doxorubicin, beta-lapachone, vitamin D2,and vitamin D3.
 5. The medical device of claim 1, wherein the at leastone water-soluble first additive is selected from the group consistingof PEG sorbitan monolaurates, PEG sorbitan monooleates, gluconolactone,and combinations thereof.
 6. The medical device of claim 1, wherein theat least one water-soluble first additive is selected from the groupconsisting of PEG-20 sorbitan monolaurate, gluconolactone, andcombinations thereof.
 7. The medical device of claim 1, wherein the atleast one water-soluble first additive is selected from the groupconsisting of PEG-20 sorbitan monolaurate, gluconolactone, andcombinations thereof.
 8. The medical device of claim 7, wherein thehydrophobic therapeutic agent is rapamycin, doxorubicin, beta-lapachone,vitamin D2, or vitamin D3.
 9. The medical device of claim 1, wherein:the at least one water-soluble first additive is gluconolactone.
 10. Themedical device of claim 9, wherein the hydrophobic therapeutic agent israpamycin, doxorubicin, beta-lapachone, vitamin D2, or vitamin D3. 11.The medical device of claim 1, wherein: the at least one water-solublefirst additive is PEG-20 sorbitan monolaurate; and the at least onewater-insoluble second additive is phosphatidylcholine.
 12. The medicaldevice of claim 11, wherein the hydrophobic therapeutic agent israpamycin, doxorubicin, beta-lapachone, vitamin D2, or vitamin D3. 13.The medical device of claim 1, wherein the coating layer consistsessentially of the hydrophobic therapeutic agent, the water-solublefirst additive, and the water-insoluble second additive.
 14. A medicaldevice for delivering a therapeutic agent to a tissue, the medicaldevice comprising a coating layer overlying an exterior surface of themedical device, the coating layer consisting essentially of: ahydrophobic therapeutic agent chosen from paclitaxel, rapamycin,doxorubicin, lapachone, vitamin D2, vitamin D3, and combinationsthereof; at least one water-soluble first additive selected from thegroup consisting of PEG fatty esters, gluconolactone, and combinationsthereof; and at least one water-insoluble second additive selected fromthe group consisting of soybean oil, vegetable oil, flower oil, coconutoil, palm oil, olive oil, fish oil, butanoic acid, hexanoic acid,octanoic acid, decanoic acid, dodecanoic acid, tetradecanoic acid,hexadecanoic acid, octadecanoic acid, octadecatrienoic acid, eicosanoicacid, eicosenoic acid, eicosatetraenoic acid, eicosapentaenoic acid,docosahexaenoic acid, tocotrienol, butyric acid, caproic acid, caprylicacid, capric acid, lauric acid, myristic acid, palmitic acid,palmitoleic acid, stearic acid, oleic acid, vaccenic acid, linoleicacid, alpha-linolenic acid, gamma-linolenic acid, behenic acid, erucicacid, lignoceric acid, and combinations thereof.
 15. The medical deviceof claim 14, wherein: the at least one water-soluble first additive isgluconolactone; and the at least one water-insoluble second additive isselected from the group consisting of fish oil, soybean oil, and oliveoil.
 16. The medical device of claim 14, wherein: the at least onewater-soluble first additive is PEG-20 sorbitan monolaurate; and the atleast one water-insoluble second additive is tocotrienol.
 17. Themedical device of claim 14, wherein the medical device is chosen from alaser catheter, an atherectomy device, a debulking catheter, a stent, afilter, a stent graft, a covered stent, a patch, a wire, and a valve.